John D. Murphy

Pulmonary AV Malformations After Superior Cavopulmonary Connection: Resolution After Inclusion of Hepatic Veins in the Pulmonary Circulation

BACKGROUND A high incidence of pulmonary arteriovenous malformations (PAVMs) has been reported in patients who have polysplenia and congenital heart disease after superior cavopulmonary anastomosis. Interruption of hepatic venous return to the pulmonary circulation is believed to potentiate the development of PAVMs. Surgical inclusion of hepatic flow in the pulmonary circulation may result in their resolution. METHODS We reviewed 3 patients with congenital heart disease and polysplenia in whom PAVMs developed and who had subsequent hepatic vein inclusion in the pulmonary circulation. RESULTS Patients underwent superior cavopulmonary connection at a median age of 8 months. The PAVMs were diagnosed at a median duration of 8 months after operation (arterial saturation <75% in room air). Hepatic venous flow was included in the pulmonary circulation at operation. Resolution of PAVMs occurred at a median duration of 7 months after operation (arterial saturation >90% in room air). CONCLUSIONS Surgical inclusion of hepatic venous blood in the pulmonary circulation results in the resolution of PAVMs. Electively associating the hepatic veins with the pulmonary vasculature may prevent the development of PAVMs in patients who are at risk.

Balloon angioplasty-branch pulmonary artery stenosis: Results from the Valvuloplasty and Angioplasty of Congenital Anomalies Registry

Balloon angioplasty for branch pulmonary artery stenosis was reported from 27 institutions to the Valvuloplasty and Angioplasty of Congenital Anomalies Registry. One hundred eighty-two procedures were performed in 156 patients ranging in age from 0.2 to 46.2 years (mean 7.7). Short-term angiographic appearance, hemodynamic results and immediate complications were recorded. Vessel dimension at the site of stenosis increased from 4.5 +/- 2.0 (mean +/- standard deviation) to 6.8 +/- 3.0 mm (p less than 0.001) with greater increases in vessel dimension at the site of stenosis if the balloon diameter was greater than 3 X the original dimension of the stenosis. There was no significant benefit related to age or prior surgical intervention. The mean peak systolic pressure gradient was reduced from 49 +/- 25 to 37 +/- 26 mm Hg (p less than 0.001) and pressure proximal to the stenosis decreased from 69 +/- 25 to 63 +/- 24 mm Hg (p less than 0.001). Complications occurred in 21 patients and included vessel rupture and death in 2 patients, vessel perforation or rupture with survival in 3, cardiac arrest and death in 1, paradoxical embolism and death in 1 and low output and death in 1. Balloon angioplasty for branch pulmonary artery stenosis increases vessel dimension at the site of stenosis, reduces systolic pressure gradient and to a minor degree, reduces proximal pressure. Long-term outcome and potential complications are as yet uncertain.

Early reduction of the volume work of the single ventricle: The hemi-fontan operation

BACKGROUND In hearts with a functional single ventricle, cavity volume and myocardial muscle mass increase as a consequence of the excessive volume work associated with parallel pulmonary and systemic circulations. The hemi-Fontan operation was conceived as a means of accomplishing early reduction of the volume work of the single ventricle. METHODS All patients presenting in infancy with single-ventricle physiology were managed by early hemi-Fontan operation in anticipation of a subsequent completion Fontan operation. Between May 1989 and August 1995, 400 patients less than 2 years of age underwent hemi-Fontan operations. Mean age at operation was 8.5 months (range, 2 months to 24 months). The hemi-Fontan operation included association of superior vena(e) cava(e) with the branch pulmonary arteries, augmentation of the central pulmonary arteries, occlusion of the inflow of the superior vena cava into the right atrium, and elimination of other sources of pulmonary blood flow. RESULTS Operative mortality ( < 30 days) was 31 of 400 patients (7.8%). For the last 200 patients, operative mortality was 8 of 200 (4.0%). Younger age at operation was not an independent risk factor for operative mortality. Urgent operation in the presence of a hemodynamic burden requiring concomitant procedures was associated with increased mortality. CONCLUSIONS The hemi-Fontan operation can be accomplished with low operative mortality in young patients, achieving early reduction of the volume work of the single-ventricle heart.

The significance of tricuspid regurgitation in hypoplastic left-heart syndrome.

Palliation of hypoplastic left-heart syndrome involves use of the morphologic right ventricle as the systemic ventricle and the tricuspid valve (in cases of mitral atresia/stenosis) or the common atrioventricular valve (in cases of malaligned atrioventricular canal) as the systemic atrioventricular valve. To determine the relationship between tricuspid or common atrioventricular valve function and the ultimate outcome of palliative surgery, 100 patients with hypoplastic left-heart syndrome were evaluated preoperatively by Doppler echocardiography to determine the degree of tricuspid regurgitation. These patients were then followed serially to assess changes with time in the functional status of the tricuspid or common atrioventricular valve and to determine the correlation of tricuspid or common atrioventricular valve regurgitation with survival. We discovered that tricuspid or common atrioventricular valve regurgitation is common in hypoplastic left-heart syndrome. Thirty-seven percent of the patients had mild, 13% had moderate, and 3% had severe tricuspid or common atrioventricular valve regurgitation on their preoperative Doppler echocardiograms. Throughout the first 2 postoperative years most patients had no significant change in the degree of tricuspid or common atrioventricular valve regurgitation when findings were compared to those of the preoperative echocardiogram. Patients with moderate or severe tricuspid or common atrioventricular valve regurgitation preoperatively had a significant reduction in their survival when contrasted with patients with no or mild atrioventricular valve regurgitation. We therefore conclude that tricuspid or common atrioventricular valve competence is a significant factor in long-term survival after palliative surgery for hypoplastic left-heart syndrome. This function, however, appears to be unaffected by palliation and remains relatively constant over the first 2 postoperative years.

Hypoplastic left heart syndrome: hemodynamic and angiographic assessment after initial reconstructive surgery and relevance to modified Fontan procedure.

After undergoing initial reconstructive surgery for hypoplastic left heart syndrome performed between August 1985 and March 1989, 59 patients (age range 3 to 27 months, mean 13.8 +/- 4.5) underwent elective cardiac catheterization in anticipation of a modified Fontan procedure. Five important hemodynamic and anatomic features considered to be components of successful reconstructive surgery were specifically addressed. 1) Interatrial communication: Only two patients had a measured pressure difference of greater than 4 mm Hg across the atrial septum. 2) Tricuspid valve function: Angiography demonstrated significant tricuspid valve regurgitation in only five patients (moderate in two and severe in three). 3) Aortic arch: Pressure tracings from the right ventricle to the descending aorta revealed a gradient greater than 25 mm Hg in only two patients. 4) Pulmonary vasculature: Ten patients had a calculated pulmonary vascular resistance greater than 4 U.m2; 51 (86%) of the 59 patients had no evidence of distortion (stenosis or hypoplasia) of either the left or the right pulmonary artery. 5) Right ventricular function: Five patients had an end-diastolic pressure in the right ventricle greater than 12 mm Hg and two patients had qualitative assessment of decreased ventricular function. Comparison of catheterization data between survivors and nonsurvivors of the subsequent modified Fontan procedure showed that only significant tricuspid regurgitation is a possible predictor of poor outcome. After first stage reconstructive surgery for hypoplastic left heart syndrome, most survivors have favorable anatomy and hemodynamics at follow-up cardiac catheterization for a subsequent Fontan procedure.

Results of Norwood's operation for lesions other than hypoplastic left heart syndrome

Norwoods operation provides satisfactory palliation for neonates with hypoplastic left heart syndrome. The dominant physiologic features of hypoplastic left heart syndrome, ductal dependency of the systemic circulation and parallel pulmonary and systemic circulations, are shared by a multitude of other less common congenital heart malformations. Theoretically, these should be equally amenable to palliation by Norwoods operation. Between January 1990 and June 1994, 60 neonates with malformations other than hypoplastic left heart syndrome underwent initial surgical palliation by Norwoods procedure. Diagnoses included single left ventricle with levo-transposition of the great arteries (12); critical aortic stenosis (8); complex double-outlet right ventricle (8); interrupted aortic arch with ventricular septal defect and subaortic stenosis (7); ventricular septal defect, subaortic stenosis, and coarctation of the aorta (7); aortic atresia with large ventricular septal defect (6); tricuspid atresia with transposition of the great arteries (6); heterotaxy syndrome with subaortic obstruction (3); and other (3). There were 10 hospital deaths and 50 survivors (83% survival). After the introduction of inspired carbon dioxide therapy into the postoperative management protocol (1991), 42 of 47 patients survived (89% survival). Mortality was independent of diagnosis and essentially the same as that for hypoplastic left heart syndrome. With minor technical modifications, Norwoods operation provides satisfactory initial palliation for a wide variety of malformations characterized by ductal dependency of the systemic circulation in anticipation of either a Fontan procedure or a biventricular repair.

Postmortem echocardiography and tomographic anatomy of hypoplastic left heart syndrome after palliative surgery

A study was undertaken to improve the understanding of the 3-dimensional (3-D) topology of a complex surgical reconstruction. The pathologic anatomy was investigated by first fixing postmortem heart specimens in such a way as to preserve the 3-D relations. Next, a technique for postmortem 2-D echocardiography was developed to aid in selection of tomographic planes for sectioning the specimens. Subsequent adjustment of planes of section was made to better show particular facets of the anatomy. The material for this investigation was drawn from cases of hypoplastic left heart syndrome after surgical palliation by the Norwood procedure. Three potential hemodynamic sequelae--restrictive inter atrial communication, aortic obstruction at any level and distortion of the pulmonary artery confluence--served as the anatomic focus for this study. Careful preservation of 3-D topology and postmortem 2-D echocardiographic imaging coupled with tomographic sectioning of specimens led to development of new, clinically relevant echocardiographic views for imaging specific atrial septal and aortic arch anomalies. These techniques offer insight into the spectrum of anatomic sequelae of this type of surgery and may be applied to echocardiographic imaging of patients and refinement of surgical technique for other forms of complex congenital heart disease.

Two-dimensional and doppler echocardiographic assessment of neonatal arterial repair for transposition of the great arteries

The arterial switch procedure has become an accepted reparative technique for transposition of the great arteries with or without ventricular septal defect. In this study the accuracy of prospective noninvasive imaging in detecting arterial tract obstruction and the prevalence and severity of arterial valvular regurgitation (as assessed by Doppler ultrasound) were evaluated in survivors of arterial repair. All 53 study patients underwent two-dimensional echocardiographic examination 2 days to 20 months (median 7 months) postoperatively; 43 patients also had pulsed and continuous wave Doppler studies. The accuracy of the noninvasive evaluation of arterial tract obstruction was determined by comparison of Doppler maximal instantaneous gradients with peak to peak gradients at nonsimultaneous catheterization in 26 patients. Twenty-one (81%) of the 26 patients underwent catheterization and successful pulsed and continuous wave Doppler examination of the right heart; 17 (81%) of these 21 had a maximal pressure gradient within 20 mm Hg of the peak to peak gradient obtained at catheterization. Echocardiographic identification of the stenotic site was correct in all eight of the patients in this group requiring reoperation. Twenty-three (88%) of the 26 patients who underwent catheterization had successful Doppler interrogation of the aortic tract; 22 (96%) of these 23 had a maximal instantaneous gradient within 20 mm Hg of the peak to peak catheterization gradient. Fourteen (32%) of 43 patients had mild or moderate pulmonary regurgitation by Doppler study. Three (7%) of the 43 had mild aortic regurgitation.

Intraoperative balloon angioplasty of aortic coarctation in infants with hypoplastic left heart syndrome

During a 1-year period, 9 children, aged 3 to 18 months, underwent intraoperative transluminal balloon angioplasty of coarctation of the aorta. Each patient had previously undergone palliative surgery for hypoplastic left heart syndrome. In 1 patient the angioplasty catheter was introduced into the ascending aorta during surgery to correct intracardiac defects. In the other 8 infants the catheters were inserted directly into the descending thoracic aorta via thoracotomy because the catheter size precluded percutaneous insertion into the femoral artery. In each case, after measuring the systolic pressure gradient across the coarctation, the angioplasty catheters were advanced over the guidewire across the coarctation site. The balloons were then inflated 2 to 3 times with an internal pressure of 3 to 6 atm. After the dilation sequence the angioplasty catheters were removed and the pressures were again measured above and below the coarctation. Preoperative gradients across the coarctation site ranged from 26 to 85 mm Hg (mean 45). Immediately after the procedure the gradient decreased in each case, ranging from 0 to 12 mm Hg (mean 4.3). There were no signs of disruption of the aortic wall. Relief of the pressure gradient persisted in the 7 patients who underwent follow-up cardiac catheterization after the procedure. The patients have been followed for as long as 18 months after the procedure and none has shown physical or echocardiographic evidence of recurrent aortic obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor Necrosis Factor Receptor–Associated Factor 2 Mediates Mitochondrial Autophagy

Background—Tumor necrosis factor (TNF) signaling protects against ischemia/reperfusion–induced cardiomyocyte death, in vitro, ex vivo, and in vivo. TNF-receptor–associated factor 2 (TRAF2), an E3 ubiquitin ligase, coordinates cytoprotective signaling downstream of both TNF receptors, via unclear mechanisms. Noting that TRAF2 is recruited to mitochondria, and that autophagic removal of ubiquitin-tagged damaged mitochondria is cytoprotective, we tested the hypothesis that TRAF2 mediates mitochondrial autophagy. Methods and Results—TRAF2 localizes to the mitochondria in neonatal rat cardiac myocytes, and TNF treatment transcriptionally upregulates TRAF2 abundance in the mitochondrial subfraction. TRAF2 colocalizes with ubiquitin, p62 adaptor protein, and mitochondria within LC3-bound autophagosomes; and exogenous TRAF2 enhances autophagic removal of mitochondria. TRAF2 knockdown with adenoviral shRNA transduction induces accumulation of depolarized mitochondria in resting neonatal rat cardiac myocytes, as well as in those treated with TNF or uncoupling agent carbonyl cyanide m-chlorophenyl hydrazone, suggesting an essential role for TRAF2 in homeostatic and stress-induced mitochondrial autophagy. TRAF2 also colocalizes and interacts with PARKIN, a previously described E3 ubiquitin ligase and mitophagy effector, on depolarized mitochondria in neonatal rat cardiac myocytes. Exogenous expression of TRAF2, but not its E3 ligase-deficient mutants, is sufficient to partially restore mitophagy in the setting of PARKIN knockdown, suggesting redundancy in their ubiquitin ligase roles. TRAF2 abundance increases in the mitochondrial subfraction of ischemia/reperfusion–modeled hearts; and exogenous TRAF2, but not its E3 ligase-deficient mutants, reduces depolarized mitochondria and rescues cell death in neonatal rat cardiac myocytes subjected to hypoxia/reoxygenation. Conclusions—Taken together, these data indicate an essential role for TRAF2 in concert with PARKIN as a mitophagy effector, which contributes to TRAF2-induced cytoprotective signaling.Emerging evidence indicates that activation of innate immunity signaling is critical for myocardial adaptation to stress (reviewed in 1). One such highly evolutionary conserved pathway is activated by Tumor Necrosis Factor (TNF), the prototypical member of the TNF superfamily of ligands.2 Indeed, TNF pretreatment, or activation of either TNFR1 or TNFR2 receptor, prevents hypoxia-reperfusion-induced cell death in mammalian cardiomyocytes, in-vitro;3 and transgenic expression or exogenous administration of low doses of TNF attenuates ex-vivo cardiac ischemia-reperfusion (IR) injury.4, 5 Also, absence of both TNFR1 and TNFR2 receptors increases IR-induced cardiomyocyte death, ex-vivo4 and results in marked increase in infarct size with in-vivo coronary ligation as compared with controls;6 pointing to a redundancy in cytoprotective signaling triggered by TNF via its cognate receptors. In this context, it is notable that TNF-receptor associated factor-2 (TRAF2), a scaffolding protein, is recruited to both TNF receptors upon their activation,7 and its transgenic expression (at low levels) attenuates cardiomyocyte death with experimental ex-vivo ischemia-reperfusion injury.4 While these data suggest that TRAF2 may facilitate cytoprotective signaling downstream of both TNF receptors, the underlying mechanisms remain largely unknown, despite extensive investigation.3-5 Ischemia-reperfusion injury results in generation of reactive oxygen species, which provoke mitochondrial permeabilization leading to programmed cardiomyocyte death.8 Autophagy is an evolutionarily conserved pro-survival pathway that sequesters damaged mitochondria within autophagosomes resulting in their intralysosomal degradation (by mitophagy), which is essential to protect against cardiomyocyte death in myocardial infarction.9, 10 Activation of mitophagy also plays a central role in ischemia preconditioning.11 TNF signaling is implicated in induction of cardiomyocyte autophagy, which is cytoprotective against LPS-induced cell death.12 Whether TNF induces mitophagy or signals via TRAF2 to promote mitochondrial autophagy, is not known. Ubiquitination of mitochondrial proteins in response to mitochondrial damage is essential for their sequestration and degradation within the lysosomes.13 PARKIN, an E3 ubiquitin ligase is recruited to damaged mitochondria via activation by PINK1 (PTEN-induced putative kinase 1, a serine-heroine kinase), and ubiquitinates mitochondrial proteins.14, 15 However, while targeted ablation of PINK1 in cardiac myocytes results in mitochondrial abnormalities and cardiomyopathy,16 loss of PARKIN is well tolerated in the unstressed state,17 suggesting that other E3 ubiquitin ligases may be involved in removal of damaged mitochondria. Relevant to this discussion is the observation that TRAF2, an E3 ubiquitin ligase,18 is recruited to the mitochondria by MAVS (Mitochondrial Anti-Viral-Signalosome), a mitochondrially localized protein with multiple scaffolding domains,19-21 following activation of innate immune signaling pathways. Therefore, we tested the hypothesis that TRAF2 mediates mitochondrial autophagy. Here, we show for the first time that TRAF2 is present on the mitochondria in resting cardiac myocytes, and functions in concert with PARKIN as an E3 ubiquitin ligase to facilitate autophagic removal of damaged mitochondria, raising the intriguing possibility that TRAF2-mediated mitophagy may be an important determinant of cytoprotective TNF signaling in ischemia-reperfusion injury.