Biventricular function in preterm infants with patent ductus arteriosus ligation: A three-dimensional echocardiographic study.

BACKGROUND: The detailed hemodynamics after patent ductus arteriosus (PDA) ligation in preterm infants remain unknown. We aimed to clarify the effect of surgical ligation on left ventricular (LV) and right ventricular (RV) volume and function. METHODS: Echocardiography was performed in 41 preterm infants (median gestational age: 25 weeks) before and after PDA ligation. Global longitudinal strain was determined using three-dimensional speckle-tracking echocardiography. These values were compared with those in 36 preterm infants without PDA (non-PDA). RESULTS: Preoperatively, the PDA group had greater end-diastolic volume (EDV) and cardiac output (CO) in both ventricles, a higher LV ejection fraction (LVEF) (53% vs 44%) and LV global longitudinal strain, and a lower RVEF (47% vs 52%) than the non-PDA group. At 4-8 h postoperatively, the two groups had a similar LVEDV and RVEDV. However, the PDA group had a lower EF and CO in both ventricles than the non-PDA group. At 24-48 h postoperatively, the RVEF was increased, but the LVEF remained decreased, and LVCO was increased. CONCLUSIONS: PDA induces biventricular loading and functional abnormalities in preterm infants, and they dramatically change after surgery. Three-dimensional echocardiography may be beneficial to understand the status of both ventricles. IMPACT: Preterm infants are at high risk of hemodynamic compromise following a sudden change in loading conditions after PDA ligation. Three-dimensional echocardiography enables quantitative and serial evaluation of ventricular function and volume in preterm infants with PDA. PDA induces biventricular loading and functional abnormalities in preterm infants, and they dramatically change after surgery.

Retrospective study of preoperative sildenafil in prolonged pleural effusion after Fontan.

Background: By rerouting the systemic venous return into the pulmonary circulation, the Fontan operation is perhaps the most effective palliative procedure in patients with complex congenital heart disease. The Fontan, however, still comes with several significant complications and morbidities, one of them being postoperative prolonged pleural effusion. In our center from 2017 to 2021, 10% of all our patients who underwent Fontan operation developed prolonged pleural effusion. With this study, we aimed to analyze the preoperative use of sildenafil for 6 months and its role in prolonged pleural effusion after the Fontan operation. Materials and Methods: In total, 158 patients were included in the analysis. The cohort was divided into patients who developed prolonged pleural effusion after Fontan surgery (n = 17) and those who did not (n = 141). We analyzed several risk factors and the history of sildenafil use in each group in the cohort. We found that patients who used sildenafil for at least 6 months prior to Fontan surgery versus those who did not use (n = 112 vs. n = 46) were found to be at lower risk of developing prolonged pleural effusion (odds ratio [OR]: 0.32 [confidence interval 95%: 0.11-0.88], P = 0.027). Conclusion: Preoperative administration of sildenafil for at least 6 months before Fontan might reduce the risk of postoperative prolonged pleural effusion.

Impact of the Axillary Approach on Epicardial Pacing Lead Durability in Children.

BACKGROUND: To avoid lead failure and pocket infection in neonates and infants requiring pacemakers, we used the axillary approach of placing the generator in the axilla and the leads in the intrathoracic space. We describe the technical details of the axillary approach and evaluate the efficacy of this method. METHODS: We assessed 21 patients (7 male) weighing 8 kg or less who underwent epicardial pacemaker implantation with the axillary approach between 2004 and 2018. The axillary approach entails (1) positioning the pacemaker generator in the axilla to avoid local skin and pocket complications due to tissue compression by the generator, and (2) making a double loop in the pleural space to reduce stress on the pacemaker leads caused by somatic growth. This approach can be combined with median sternotomy for simultaneous intracardiac repair. RESULTS: The patients' median age at pacemaker implantation was 6 months; 16 patients (76%) were aged less than 12 months. The median body weight was 4.5 kg (interquartile range, 3 to 7). In all 5 patients requiring simultaneous cardiac repair, a median sternotomy was performed to access the heart. Sixteen patients required only pacemaker implantation: left thoracotomy was performed in 10 patients, right thoracotomy in 5, and subxiphoid approach in 1. The 5-year and 10-year freedom from pacemaker-related adverse events was 89.4% and 79.5%, respectively. CONCLUSIONS: The axillary approach using intrathoracic double-loop routing of leads to position the generator in the axilla for pacemaker implantation can be a valuable alternative for neonates/infants weighing 8 kg or less with or without complex congenital heart disease.

Transcriptome Analysis Reveals Differential Gene Expression between the Closing Ductus Arteriosus and the Patent Ductus Arteriosus in Humans.

The ductus arteriosus (DA) immediately starts closing after birth. This dynamic process involves DA-specific properties, including highly differentiated smooth muscle, sparse elastic fibers, and intimal thickening (IT). Although several studies have demonstrated DA-specific gene expressions using animal tissues and human fetuses, the transcriptional profiles of the closing DA and the patent DA remain largely unknown. We performed transcriptome analysis using four human DA samples. The three closing DA samples exhibited typical DA morphology, but the patent DA exhibited aorta-like elastic lamellae and poorly formed IT. A cluster analysis revealed that samples were clearly divided into two major clusters, the closing DA and patent DA clusters, and showed distinct gene expression profiles in IT and the tunica media of the closing DA samples. Cardiac neural crest-related genes such as JAG1 were highly expressed in the tunica media and IT of the closing DA samples compared to the patent DA sample. Abundant protein expressions of jagged 1 and the differentiated smooth muscle marker calponin were observed in the closing DA samples but not in the patent DA sample. Second heart field-related genes such as ISL1 were enriched in the patent DA sample. These data indicate that the patent DA may have different cell lineages compared to the closing DA.

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus.

OBJECTIVE: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1-deficient (Fbln1-/-) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse (Ptger4-/-) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. CONCLUSIONS: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

Rapid two-stage Starnes approach in high-risk neonates with Ebstein anomaly.

OBJECTIVES: The purpose of this study is to review the short- and long-term outcomes of high-risk neonates with Ebstein anomaly treated with a newly developed rapid 2-stage Starnes procedure, which is aimed at reducing the size of the enlarged right side of the heart. METHODS: Fifty-two foetuses with Ebstein anomaly were analysed in this study and divided into 2 groups. The control group comprised 25 foetuses, referred to us before 2008, and the study group was composed of 27 foetuses, referred to us after 2009. The right atrial area index was defined as high risk when it was >1.5. We applied our management approach to 6 high-risk neonates in the study group. This approach consisted of reducing the size of the right side of the heart through a 2-stage process: (i) right atrial plication without the use of a bypass and (ii) a Starnes procedure. Cox proportional hazards models were used to evaluate the effects of our management approach on the survival rates of the neonates. RESULTS: The mean follow-up period was 7.5 ± 3.3 years. All 6 high-risk neonates in the study group survived. The overall hazard ratio was 0.12 (95% confidence interval of 0.03-0.43) in the study group as compared with the control group (P = 0.0007). A Fontan operation was completed in all but 1 case, with the remaining case awaiting a Fontan operation. CONCLUSIONS: We suggest that a rapid 2-stage Starnes approach can be effective in the treatment of high-risk neonates with Ebstein anomaly.

Outcomes of bidirectional cavopulmonary shunt in patients younger than 4 months of age.

OBJECTIVES: Bidirectional cavopulmonary shunt (BCPS) has played an important role in the staged Fontan approach; however, the timing remains controversial, especially in younger patients. Therefore, we examined the outcomes of BCPS in infants younger than 3 months of age. METHODS: From 2004 to 2018, 120 patients underwent BCPS at <4 months of age (younger group). For reference, we also reviewed the data from 204 patients who had undergone the BCPS procedure during the same period at more than 4 months of age (older group). RESULTS: The median age and body weight at the time of the BCPS were 102 days and 4.2 kg for the younger group versus 196 days and 6.3 kg for the older group, respectively. Forty-eight patients (14.8%, 48 of 324; 16 in the younger group, 32 in the older group) had primary BCPS; the remaining 276 (104 in younger group, 172 in older group) had various forms of single-ventricle palliation before the BCPS procedure. Although preoperatively, 7 patients required extracorporeal membrane oxygenation (ECMO) support due to haemodynamic instability, they were successfully weaned from ECMO through haemodynamic benefits after BCPS. The 10-year actual survival rate (Kaplan-Meier) was 89% in the younger group and 86% in the older group (P = 0.55). Atrioventricular valve regurgitation (AVVR) was identified as a factor associated with hospital deaths in the younger group (P = 0.009), and much older age at BCPS was associated with late deaths in the older group (P = 0.027). CONCLUSIONS: In this study population, early performance of BCPS is applicable for patients who have undergone prior palliation and for those in whom primary BCPS is the first surgical intervention, even for patients with haemodynamic instabilities.

Mitral valve replacement and trans-mitral myectomy for a child with Noonan syndrome accompanied by hypertrophic obstructive cardiomyopathy.

A 4-year-old boy with Noonan syndrome accompanied by hypertrophic obstructive cardiomyopathy presented with refractory heart failure owing to severe left ventricular outflow obstruction and mitral regurgitation. He underwent mitral valve replacement and trans-mitral myectomy. The pathology of the resected myocardium was consistent with hypertrophic cardiomyopathy, and the mitral valve leaflets were severely degenerated. Compared with a control patient who is a non-syndromic 4-year-old boy with hypertrophic obstructive cardiomyopathy, mitral pathology was much more severe in Noonan syndrome. Regarding trans-mitral myectomy, residual pressure gradient at the mid-ventricular level made us think about more aggressive muscle resection with various approaches.

Aortic erosion occurring in over 5 years after Amplatzer septal Occluder implantation for secundum atrial septal defect: a case report.

BACKGROUND: Aortic erosion is a serious complication that usually occurs shortly after Amplazter Septal Occluder (ASO) implantation for atrial septal defect (ASD). CASE PRESENTATION: A seven-year-old girl was diagnosed with secundum ASD without symptoms. Transesophageal echocardiography (TEE) showed a defect of 20 mm in diameter in the fossa ovalis without aortic rim. An ASO device of 24 mm in diameter was selected and electively implanted. The "A-shape" of the device was confirmed by intraoperative TEE, a landmark finding indicating the proper implantation of ASO in patients without aortic rim. After an uneventful postoperative course of 5 years and 10 months, she was transferred to our unit due to cardiogenic shock. Her echocardiogram in emergency room showed pericardial effusion with collapsed right ventricle. Given her history of ASO and the observation of the sequentially increasing pericardial effusion, we diagnosed her with acute cardiac tamponade due to aortic erosion. Emergency pericardiotomy was then performed to improve the hemodynamic condition. Fresh clots were found, so we immediately prepared the cardiopulmonary bypass circuit and explored the damage to the aorta, in which the clots had accumulated. Bleeding suddenly started when the clots were removed. We then inserted the cannulae for perfusion and venous drainage. The clots were removed, and tears were found in both the lateral side of the ascending aorta and the right atrial wall. Intraoperative TEE showed that an edge of the ASO device was directly touching the aortic wall and the Doppler color-flow imaging showed blood flow through this lesion. The erosive lacerations of both the ascending aorta and right atrium were detected from the inside after achieving cardioplegic cardiac arrest. The ascending aorta was obliquely incised, and the laceration was closed from inside the aortic root. The postoperative course was uneventful. She has been doing well for 5 years since the surgery. CONCLUSIONS: We experienced and successfully treated a rare case of acute cardiac tamponade caused by aortic erosion 5 years and 10 months after ASO implantation.

Tissue-type plasminogen activator contributes to remodeling of the rat ductus arteriosus.

AIMS: The ductus arteriosus (DA) closes after birth to adapt to the robust changes in hemodynamics, which require intimal thickening (IT) to occur. The smooth muscle cells of the DA have been reported to play important roles in IT formation. However, the roles of the endothelial cells (ECs) have not been fully investigated. We herein focused on tissue-type plasminogen activator (t-PA), which is a DA EC dominant gene, and investigated its contribution to IT formation in the DA. METHODS AND RESULTS: ECs from the DA and aorta were isolated from fetal rats using fluorescence-activated cell sorting. RT-PCR showed that the t-PA mRNA expression level was 2.7-fold higher in DA ECs than in aortic ECs from full-term rat fetuses (gestational day 21). A strong immunoreaction for t-PA was detected in pre-term and full-term rat DA ECs. t-PA-mediated plasminogen-plasmin conversion activates gelatinase matrix metalloproteinases (MMPs). Gelatin zymography revealed that plasminogen supplementation significantly promoted activation of the elastolytic enzyme MMP-2 in rat DA ECs. In situ zymography demonstrated that marked gelatinase activity was observed at the site of disruption in the internal elastic laminae (IEL) in full-term rat DA. In a three-dimensional vascular model, EC-mediated plasminogen-plasmin conversion augmented the IEL disruption. In vivo administration of plasminogen to pre-term rat fetuses (gestational day 19), in which IT is poorly formed, promoted IEL disruption accompanied by gelatinase activation and enhanced IT formation in the DA. Additionally, experiments using five human DA tissues demonstrated that the t-PA expression level was 3.7-fold higher in the IT area than in the tunica media. t-PA protein expression and gelatinase activity were also detected in the IT area of the human DAs. CONCLUSION: t-PA expressed in ECs may help to form IT of the DA via activation of MMP-2 and disruption of IEL.

Successful coronary transfer for transposition of the great arteries with bilateral intramural coronary arteries from a single aortic sinus.

We experienced an arterial switch operation in a patient with d-transposition of the great arteries associated with bilateral intramural coronary arteries from a single coronary ostium. In performing the coronary transfer, intramural course of bilateral coronary arteries was unroofed and coronary ostium was separated into two coronary buttons. The two coronary buttons were translocated to the neo-aorta using modified trap-door technique. The angiogram performed 6 years after the operation revealed well-developed coronary arteries without stenosis, and the patient is doing well 8 years after the operation.

Glutamate Promotes Contraction of the Rat Ductus Arteriosus.

BACKGROUND: Extremely preterm infants frequently have patent ductus arteriosus (PDA). Recent recommendations include immediately beginning amino acid supplementation in extremely preterm infants. However, the effect of amino acids on closure of the ductus arteriosus (DA) remains unknown.Methods and Results:Aminogram results in human neonates at day 2 revealed that the plasma glutamate concentration was significantly lower in extremely preterm infants (<28 weeks' gestation) with PDA than in those without PDA and relatively mature preterm infants (28-29 weeks gestation). To investigate the effect of glutamate on DA closure, glutamate receptor expression in fetal rats was examined and it was found that the glutamate inotropic receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type subunit 1 (GluR1), mRNA was highly expressed in the DA compared to the aorta on gestational day 19 (preterm) and gestational day 21 (term). GluR1 proteins were co-localized with tyrosine hydroxylase-positive autonomic nerve terminals in the rat and human DA. Intraperitoneal administration of glutamate increased noradrenaline production in the rat DA. A whole-body freezing method demonstrated that glutamate administration induced DA contraction in both preterm (gestational day 20) and term rat fetuses. Glutamate-induced DA contraction was attenuated by the calcium-sensitive GluR receptor antagonist, NASPM, or the adrenergic receptor α1 blocker, prazosin. CONCLUSIONS: These data suggest that glutamate induces DA contraction through GluR-mediated noradrenaline production. Supplementation of glutamate might help to prevent PDA in extremely preterm infants. (Circ J 2016; 80: 2388-2396).

Surgical approach for systemic-pulmonary shunt in neonates with functionally univentricular heart: comparison between sternotomy and thoracotomy.

OBJECTIVE: The preferred surgical approach for systemic-pulmonary shunts has changed from thoracotomy to sternotomy in our institution, to concomitantly manage the ductus arteriosus during surgery. The purpose of this study was to compare the outcomes of systemic-pulmonary shunts for neonates with functionally univentricular hearts based on surgical approach. METHODS: Fifty-two neonates with functionally univentricular hearts underwent systemic-pulmonary shunt via sternotomy (n = 28) or thoracotomy (n = 24). Patient characteristics, achievement rates of right heart bypass, and survival rates were compared for the different approaches. RESULTS: Prenatal diagnosis was made more common in the sternotomy group (p = 0.006). The shunt was placed more centrally in the sternotomy group. The ductus arteriosus was ligated or banded in most patients in the sternotomy group (26/28) and in a few patients in the thoracotomy group (6/24). Frequency of ductal management in the early postoperative phase was not different between the groups (21 vs 25 %), but three new incisions had to be made in the thoracotomy group. No differences were seen in the achievement rates of bidirectional cavopulmonary shunts (86 vs 87 % at 10 months of age) and total cavopulmonary connection (81 vs 81 % at 2 years of age), or in the survival rates (92 vs 96 % at 8 years). CONCLUSIONS: There were no differences in short- and long-term outcomes between the groups. The sternotomy approach might be preferable in the current era of prenatal diagnosis, to allow simultaneous duct management during systemic-pulmonary shunt surgery, particularly in patients with large ducts associated with functionally univentricular hearts.

Coronary angioplasty for congenital obstruction of the left main coronary artery.

We present three children who underwent coronary angioplasty for the surgical treatment of a congenital obstruction of the left main coronary artery. An azygos vein patch or graft was a feasible and useful material for reconstructing congenital ostial stenosis and atresia of the left main coronary artery.

Hybrid palliation for a neonate with functional single ventricle and restrictive atrial septal defect: a case report.

We present the case of a neonate who was successfully treated with emergency hybrid palliation soon after birth, including a stent insertion into a severely thickened atrial septum and bilateral pulmonary artery banding. The patient was prenatally diagnosed with severe pulmonary venous hypertension owing to mitral atresia and intact atrial septum associated with functional single ventricle and coarctation of the aorta.

Decreased serum osmolality promotes ductus arteriosus constriction.

AIMS: At birth, dynamic changes occur in serum components and haemodynamics, such as closure of the ductus arteriosus (DA). A previous study demonstrated that, in full-term human neonates, serum osmolality decreased transiently after birth, but recovered over the next few days. However, the significance of this transient decrease in osmolality has never been addressed. The objective of the present study was to examine the role of changes in serum osmolality after birth in DA closure. METHODS AND RESULTS: We found that rats exhibited a similar transient hypoosmolality after birth. Hypotonic stimulation induced constriction of DA rings and increased Ca(2+) transient in DA smooth muscle cells, but not in the aorta. The hypoosmotic sensor transient receptor potential melastatin 3 (TRPM3) was highly expressed in the rat DA, and TRPM3 silencing abolished the Ca(2+) response to hypoosmolality. Pregnenolone sulfate stimulation of TRPM3 induced rat DA constriction ex vivo and in vivo. Furthermore, hypertonic fluid injection impaired rat DA closure. In humans, neonatal serum hypoosmolality was observed in relatively mature preterm infants (≥28 weeks). In extremely preterm infants (<28 weeks), however, this hypoosmolality was absent. Instead, a rapid increase in osmolality occurred thereafter. Such an increase was greater, in particular, among patent DA (PDA) patients. CONCLUSIONS: A transient decrease in serum osmolality may promote DA closure during the first few days of life. Adjusting serum osmolality to proper levels might help to prevent the onset of PDA, improving the therapeutic outcome in extremely preterm infants.

[Improvement of outcomes in the surgical treatment of hypoplastic left heart syndrome (HLHS) with staged Norwood operation].

On behalf of rapid progress of diagnostic technologies and new development of surgical technique or strategy, outcomes of surgical treatment of hypoplastic left heart syndrome (HLHS) has remarkably improved in the current practice. One of such approaches is the staged Norwood operation. We have reviewed our patients (n=54) between 2003 and 2013. A half of the patients with the staged group accomplished Norwood procedure and concomitant bidirectional cavopulmonary shunt at the mean age of 4 months old. An another half of the patients underwent secondary Norwood operation with Blalock-Taussig( BT) shunt or right-ventricle to pulmonary artery( RV-PA) conduit, because of ductal closure in spite of prostaglandin, or progressive reversed coarctation. Cardiac catheterization showed good results in both the primary (n=17) and the staged approach (n=37), partly because even in the primary Norwood group we used a smaller calibered graft for BT shunt or RV-PA conduit to unload the ventricle as much as possible. In conclusion, since the surgical mortality of staged group was superior to that of the primary group and the mid-term survival in the staged seemed to be better than that of primary, we would pursue our strategy of the staged approach in the surgical treatment of hypoplastic left heart syndrome.

Extracorporeal life support after cardiac surgery in children: outcomes from a single institution.

Extracorporeal life support (ECLS) is used after congenital heart surgery for several indications, including failure to separate from cardiopulmonary bypass, postoperative low cardiac output syndrome, and extracorporeal cardiopulmonary resuscitation. Here, we assessed the outcomes of ECLS in children after cardiac surgery at our institution. Medical records of all children who required postoperative ECLS at our institution were reviewed. Between 2003 and 2011, 36 (1.4%) of 2541 pediatric cardiac surgical cases required postoperative ECLS. Median age of patients was 64 days (range: 0 days-4.1 years). ECLS was in the form of either extracorporeal membrane oxygenation (ECMO; n = 24) or ventricular assist system (VAS; n = 12). Mean duration of ECLS was 4.9 ± 4.2 days. Overall, 21 patients (58%) were weaned off ECLS, and 17 patients (47%) were successfully discharged from the hospital. Patients with biventricular heart (BVH) had higher survival-to-hospital discharge rates compared with those with univentricular heart (UVH) (P = 0.019). Regarding ECLS type, UVH patients who received VAS showed higher rates of device discontinuation than UVH patients who received ECMO (P = 0.012). However, rates of hospital discharge were not significantly different between UVH patients who received VAS or ECMO. Surgical interventions, such as banding of Blalock-Taussig shunt to reduce pulmonary blood flow or placing bidirectional cavopulmonary shunt to minimize ventricular volume overload, were effective for weaning off ECLS in patients with UVH. ECLS is beneficial to children with low cardiac output after cardiac surgery. Rates of survival-to-hospital discharge were higher in BVH patients than UVH patients. Additional interventions to reduce ventricular volume load may be effective for discontinuing ECLS in patients with UVH.

Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling.

BACKGROUND: Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. METHODS AND RESULTS: Stimulation of the prostaglandin E2 (PGE2) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopic examination showed that the DA acquired an elastic phenotype that was similar to the neighboring aorta. More importantly, human DA and aorta tissues from 7 patients showed a negative correlation between elastic fiber formation and EP4 expression, as well as between EP4 and LOX expression. The PGE2-EP4-c-Src-phospholipase C (PLC)γ-signaling pathway most likely promoted the lysosomal degradation of LOX. CONCLUSIONS: Our data suggest that PGE2 signaling inhibits elastogenesis in the DA, but not in the aorta, through degrading LOX protein. Elastogenesis is spatially regulated by PGE2-EP4 signaling in the DA.