Rationale:
Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomical closure. Though modulated by endothelial-derived vasodilators and constrictors, O2-sensing is intrinsic to ductal smooth muscle cells (DASMC) and oxygen-induced DA constriction persists in the absence of endothelium, endothelin and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2 (mitoROS), which constricts DASMC by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown.
Objective:
Determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure.
Methods and Results:
Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase-mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the DASMC that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitoROS and cytosolic calcium. The small-molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium and DASMC proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model.
Conclusions:
Mitochondrial fission is an obligatory, early step in mammalian O2-sensing and offers a promising target for modulating DA patency.
An aortopulmonary window is a communication between the ascending aorta and pulmonary trunk in the presence of two separate arterial valves, and is often complicated by other associated defects. We sought to determine management and related outcomes in patients with this malformation. We identified those patients presenting between 1969 and 1999 from the databases held in our Departments of Cardiology, Pathology and Cardiovascular Surgery. We obtained data relating to issues concerning demography, clinical findings, imaging, management and outcome. The median age at presentation for the 42 patients identified, of whom 23 were female, was 62 days, with a range from birth to 6 years. Associated cardiac defects were present in 34 patients, including interruption of the aortic arch in 6 patients. The correct diagnosis was initially missed in 13 patients. Of the patients, six died without surgical repair, and 1 patient was lost-to-follow-up. Repair was performed in 35 patients, subsequent to repair of other defects in 4, in association with repair of other defects in 17, of whom 3 died, and as an isolated procedure in 14 patients, one of the latter being treated by transcatheter closure. Overall, there were 9 deaths, all in patients with complex associated defects, except 1 patient with a missed aortopulmonary window after repair of aortic coarctation. Kaplan-Meier estimates of survival were 81% at 3 months until 11.5 years, and 69% up to 21 years. Only the presence of interrupted aortic arch was independently associated with increased time-related mortality, the hazard ratio being 5.87 (p = 0.009). The outcome for an isolated lesion is excellent. Mortality occurs mainly before repair, mostly with complex associated lesions, particularly interruption of the aortic arch.
The outcomes for patients born with pulmonary atresia with intact ventricular septum have improved over time, albeit that careful initial management, and better selection, is still indicated for those planned to undergo biventricular repair.
Peripheral pulmonary artery stenosis challenges therapeutic algorithms for the management of congenital heart malformations. Surgical repair of the proximal pulmonary artery lesion remains with a high recurrence rate while the distal lesions are difficult to access. With the development of transcatheter interventional strategies in the early 1980s, a number of transcatheter treatment options became available. In this review, we summarize the current state of the art for interventional strategies in the management of peripheral pulmonary artery stenosis.
Vigorous pursuit of closure of post-myocardial infarction VSD with a sequential surgical and/or percutaneous approach is recommended for improved outcomes.
Septoplasty of the atrial septum was performed with sequential balloon dilation following radiofrequency-assisted perforation of an intact atrial septum in two newborn infants with hypoplastic left heart syndrome and one with double-outlet right ventricle.
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