Towards the development of a pediatric ventricular assist device.

The very limited options available to treat ventricular failure in children with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device at the University of Pittsburgh (UoP) and University of Pittsburgh Medical Center (UPMC). Our effort involves a consortium consisting of UoP, Children's Hospital of Pittsburgh (CHP), Carnegie Mellon University, World Heart Corporation, and LaunchPoint Technologies, Inc. The overall aim of our program is to develop a highly reliable, biocompatible ventricular assist device (VAD) for chronic support (6 months) of the unique and high-risk population of children between 3 and 15 kg (patients from birth to 2 years of age). The innovative pediatric ventricular assist device we are developing is based on a miniature mixed flow turbodynamic pump featuring magnetic levitation, to assure minimal blood trauma and risk of thrombosis. This review article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

The PediaFlow pediatric ventricular assist device.

The very limited options available to treat ventricular failure in patients with congenital and acquired heart diseases have motivated the development of a pediatric ventricular assist device (VAD). Our effort involves a consortium consisting of the University of Pittsburgh, Carnegie Mellon University, Children's Hospital of Pittsburgh, World Heart Corporation, and LaunchPoint Technologies, LLC. The overall aim of our program is to develop a highly reliable, biocompatible VAD for chronic support (6 months) of the unique and high-risk population of children between 3 kg and 15 kg (patients from birth to 2 years of age). The innovative pediatric VAD we are developing (PediaFlow) is based on a miniature mixed-flow turbodynamic pump featuring magnetic levitation, with the design goal being to assure minimal blood trauma and risk of thrombosis. This article discusses the limitations of current pediatric cardiac assist treatment options and the work to date by our consortium toward the development of a pediatric VAD.

A prospective analysis of the immunogenicity of cryopreserved nonvalved allografts used in pediatric heart surgery.

BACKGROUND: The purpose of this study was to prospectively determine the immunogenicity of nonvalved allograft tissue used to repair congenital heart defects. METHODS AND RESULTS: We prospectively analyzed the immune response of 11 children, 1.4 months to 10 years of age, who required nonvalved allografts to alleviate stenosis during repair of congenital heart defects. In 7 patients, pulmonary arterial grafts were used; in 3 patients, monocusp pulmonary artery grafts were used; and in 1 patient, a section of glutaraldehyde-preserved allograft pericardium was used. We measured the level of HLA panel-reactive antibody (PRA) before surgery, 1 week after, 1 month after, and 3 months after surgery. PRA was determined by the antiglobulin technique and flow cytometry. HLA class I and class II antibodies measured by either technique were negligible before and 1 week after surgery. Nine of 11 patients (82%) exhibited a significant immune response at 1 month after surgery that further increased at 3 months. The measured PRA for class I antibodies with the antiglobulin technique increased to 43+/-36% at 1 month and to 69+/-38% at 3 months after surgery. Flow cytometry class I PRA measurements were similar. Class II PRA increased to 26+/-34% at 1 month and to 41+/-36% at 3 months. Age negatively correlated with the degree of elevation of PRA, but neither allograft area nor the area indexed to patient body surface area correlated with PRA. CONCLUSIONS: Cryopreserved nonvalved allografts induce a strong HLA antibody response in the majority of children.

Gradient reduction, aortic valve regurgitation and prolapse after balloon aortic valvuloplasty in 32 consecutive patients with congenital aortic stenosis.

From 1986 to 1988, balloon aortic valvuloplasty was performed in 32 patients with congenital valvular aortic stenosis. The patients ranged in age from 2 days to 28 years (mean +/- SD 8.3 +/- 5.9). One balloon was used in 17 patients and two balloons were used in 15 patients. Immediately after valvuloplasty, peak systolic pressure gradient across the aortic valve decreased significantly from 77 +/- 27 to 23 +/- 16 mm Hg (p less than 0.01), a 70% reduction in gradient. At early follow-up study (4.1 +/- 3.3 months after valvuloplasty), there was a 48 +/- 20.5% reduction in gradient compared with that before valvuloplasty, and at late follow-up evaluation (19.2 +/- 5.6 months), a reduction in gradient of 40 +/- 29% persisted. Echocardiography showed evidence of significantly increased aortic regurgitation in 10 patients (31%) and aortic valve prolapse in 7 patients (22%). There was no correlation between the balloon/anulus ratio and the subsequent development of aortic regurgitation or prolapse. In fact, no patient who showed a significant increase in aortic regurgitation had had a balloon/anulus ratio greater than 100%. It is concluded that balloon aortic valvuloplasty effectively reduces peak systolic pressure gradient across the aortic valve in patients with congenital aortic stenosis. However, subsequent aortic regurgitation and prolapse occur in a significant number of patients, even if appropriate technique and a balloon size no greater than that of the aortic anulus are used.

Immunohistochemical analysis of platelet-derived growth factor and basic fibroblast growth factor in cardiac biopsy and autopsy specimens of heart transplant patients.

The purposes of this study were to examine 250 heart biopsy specimens and 20 autopsy specimens from heart transplant patients for the presence and localization of platelet-derived growth factor (PDGF)and basic fibroblast growth factor (bFGF) and to correlate these findings with the histologic features of rejection and the autopsy findings of graft coronary vasculopathy and global ischemia. Positive specimen staining was significantly more prevalent for PDGF (78% of specimens) than for bFGF (54% of specimens) (p< 0.001). PDGF was distributed more in an interstitial (53%) than a vascular (28%) pattern and was associated with macrophages, whereas bFGF was distributed more in a vascular (50%) than an interstitial (12%) pattern. The prevalence of PDGF (but not bFGF) staining was significantly greater in biopsy specimens with at least grade 2 vascular rejection changes (81%) than in those without vascular rejection changes (58%) (p<0.001). In autopsy specimens, PDGF staining was present in the hearts of all 5 patients (100%) who died of graft failure from coronary vasculopathy and was present in all 11 hearts (100%) with global ischemic changes, but in only 4 of 9 (44%) of the hearts without global ischemia (p<0.01). PDGF staining was absent in nontransplanted heart specimens, whereas bFGF staining in nontransplanted heart specimen was similar to that in transplanted hearts. We conclude that PDGF is increased in transplanted hearts, is distributed more in an interstitial pattern, and is associated with macrophages. Furthermore, PDGF staining is increased in transplanted hearts with evidence of vascular rejection, coronary vasculopathy, or global ischemia.

Abnormal Doppler pulmonary venous flow patterns in children after repaired total anomalous pulmonary venous connection.

Doppler echocardiography was used to evaluate pulmonary venous flow patterns in 16 children with repaired total anomalous pulmonary venous connection and in 16 age-matched normal controls. Using right upper pulmonary venous pulsed Doppler tracings, peak velocities and velocity time integrals were determined for ventricular systole, ventricular diastole, and atrial systole. Mitral inflow indexes and cardiac outputs were obtained. Patients with repaired total anomalous pulmonary venous connection and controls were similar in weight, heart rate, mitral inflow indexes, and cardiac output. In normal children, peak velocities were greater during ventricular diastole than systole, but velocity time integrals were greater during ventricular systole than diastole. Compared with normals, repaired patients had unobstructed flow patterns with increased peak velocities during ventricular diastole (0.92 +/- 0.35 vs 0.62 +/- 0.12 m/s) and atrial systole (0.27 +/- 0.12 vs 0.17 +/- 0.04 m/s). Velocity time integrals of repaired patients were increased during atrial systole (0.02 +/- 0.01 vs 0.01 +/- 0.03 m) but decreased during ventricular systole (0.08 +/- 0.03 vs 0.12 +/- 0.03 m). Systolic-to-diastolic ratios were decreased in repaired patients for peak velocity (0.56 +/- 0.20 vs 0.79 +/- 0.12) and velocity time integral (0.6 +/- 0.18 vs 1.48 +/- 0.35). Thus, pulmonary venous flow in normal children is greater during ventricular systole than during ventricular diastole. Repaired patients show a shift in forward flow from ventricular systole to diastole, with greater reversed flow during atrial systole.

Doppler evaluation of aortic regurgitation in children.

Doppler indexes have been used successfully to determine the severity of aortic regurgitation (AR) in adults but have not been evaluated systematically in children. To evaluate the accuracy of specific Doppler echocardiographic indexes in assessing the degree of AR in children, 30 children underwent 2-dimensional and Doppler echocardiography within 24 hours of angiography. Patients were divided into 4 groups based on the degree of angiographic AR. Color Doppler jet width, short-axis jet area, jet length, and maximum jet area were measured. AR slope was measured using continuous-wave Doppler. Flow in the abdominal aorta was evaluated using pulsed Doppler. Doppler indexes were compared with the angiographic grade of AR. Jet width and short-axis jet area were significantly different between groups and showed strong correlation with the angiographic grade. Holodiastolic flow reversal in the abdominal aorta separated 1+ to 2+ from 3+ to 4+ AR (100% sensitivity and 100% negative predictive value for 3+ to 4+ AR). Jet length, maximum jet area, and the ratio of reverse to forward abdominal aortic velocity time integrals correlated with angiography but showed little difference between groups that differed by only 1 angiographic grade. AR slope did not correlate with the angiographic grade. We conclude that in children, color Doppler jet width, short-axis jet area, and holodiastolic abdominal aortic flow reversal are the best predictors of angiographic severity. Use of these indexes may obviate the need for angiography to determine the degree of AR in children.

Persistence of human leukocyte antigen (HLA) antibodies after one year in children receiving cryopreserved valved allografts.

This study shows that the broad anti-HLA antibody response against cryopreserved valved allografts used for surgical repair of congenital heart disease persists beyond 1 year after implantation. In 3 patients, there were clearly defined HLA antibody specificities consistent with the HLA phenotypes of the patients, i.e., the panel-reactive antibody was directed against major alloantigen groups that were not expressed by the antibody responders.

A novel approach to pediatric intraaortic balloon pump timing using M-mode echocardiography.

Timing balloon inflation and deflation is difficult in pediatric patients undergoing intraaortic balloon pumping, because the electrocardiogram and arterial pressure tracings are inadequate markers of the onset of diastole and systole. M-mode echocardiography provides a precise marker of aortic valve opening and closure, as well as balloon motion, and allows accurate timing by real-time adjustment of balloon inflation to diastole and deflation to systole.

Influence of left ventricular cavity size on interventricular shunt timing and outcome in neonates with coarctation of the aorta and ventricular septal defect.

In this study, we reviewed the records and echocardiograms of 39 consecutive patients with coarctation of the aorta and ventricular septal defect who underwent neonatal coarctation repair to examine the influence of left heart size on ventricular shunting and outcome. We found smaller left heart structures (initial mitral and aortic annular diameters) to be associated with diastolic interventricular shunting and to be predictive of the development of mitral or aortic and/or subaortic stenosis.

Usefulness of the preoperative tricuspid/mitral valve ratio for predicting outcome in pulmonary atresia with intact ventricular septum.

Although tricuspid valve z-scores have been used to predict outcome in pulmonary atresia with intact ventricular septum, they are statistically generated from local populations, and widespread generalization may not be appropriate. To determine if there are echocardiographic predictors of outcome that can be universally used, the records of all infants with this diagnosis since 1988 were reviewed for age, weight, type of surgery, and outcome. Preoperative and follow-up echocardiograms were reviewed for valve diameter and z-scores, and valve ratios were calculated. Thirty-six patients were divided into 2 groups: group 1 included 23 infants who had a successful biventricular repair; group 2 included the remaining 13 infants who did not have a successful repair. Preoperatively, both groups had similar ages, pulmonary, aortic, and mitral z-scores, and pulmonary/aortic ratios, but the patients in group 2 had significantly lower weight (3.5 +/- 0.6 vs 2.9 +/- 0.5 kg), tricuspid z-scores (-0.7 +/- 1.5 vs -2.3 +/- 1.2), and tricuspid/mitral ratios (0.8 +/- 0.2 vs 0.5 +/- 0.1). At similar follow-up, both groups of patients had similar weight, aortic and mitral z-scores, and pulmonary/aortic ratios, but group 2 infants had significantly lower pulmonary and tricuspid z-scores and tricuspid/mitral ratios. Compared with the preoperative echocardiograms, group 1 had significant increases only in pulmonary z-scores, and pulmonary/aortic and tricuspid/mitral ratios. Group 2 had no significant change in any echocardiographic variable. The tricuspid/mitral ratio was >0.5 in all group 1 infants, and in 6 of 13 group 2 infants (2 sepsis deaths, 4 palliations). Compared with a tricuspid valve z-score >-3, a tricuspid/mitral ratio >0.5 was a better predictor of biventricular repair. Thus, infants who have a successful biventricular repair have significantly greater preoperative weight, tricuspid valve z-scores, and tricuspid/mitral valve ratios. A tricuspid/mitral ratio >0.5 was the best predictor of a biventricular repair.

Usefulness of echocardiography for detection of coronary artery thrombi in patients with Kawasaki disease.

To evaluate the role of echocardiography for predicting and accurately detecting thrombi in patients with abnormal coronary arteries after Kawasaki disease, we reviewed the echocardiograms of 40 consecutive patients and compared echocardiographic findings with angiographic findings when available. Patients with Kawasaki disease who had coronary artery aneurysms > or =5 mm had significantly greater multivessel involvement, thrombi, and persistent coronary abnormalities than those with diameters <5 mm.

Size of ventricular structures influences surgical outcome in Down syndrome infants with atrioventricular septal defect.

To evaluate the relation between ventricular structure size and surgical outcome in Down versus non-Down syndrome infants with an atrioventricular septal defect, we reviewed the charts and echocardiograms of 44 consecutive infants (34 with Down syndrome) who underwent atrioventricular septal defect repair. Children with Down syndrome had significantly greater aortic valve diameters, left ventricular valve areas, and left/right atrioventricular valve area ratios as well as fewer adverse outcomes than non-Down syndrome children.

Class I and class II anti-HLA antibodies after implantation of cryopreserved allograft material in pediatric patients.

OBJECTIVES: Very little is known regarding the immune response to cryopreserved allograft valves and patch material used in the surgical repair of congenital heart defects. METHODS: We prospectively measured the frequency of panel reactive antibodies directed against HLA class I (HLA-A, B, and C) and class II (HLA-DR/DQ) alloantigens in 24 children receiving cryopreserved allografts. We compared them with results in 11 previously reported control patients. Sixteen of the study patients underwent placement of a valved conduit (11 pulmonic, 5 aortic) between the right ventricle and pulmonary arteries, 6 underwent patch angioplasty of stenotic vessels with cryopreserved pulmonary artery, and 2 underwent placement of a pulmonary monocusp patch. Study patients had panel reactive antibodies measured before, 1 month, 3 months, and 1 year after the operation. RESULTS: With allograft implantation, panel reactive antibodies increased from 1.9% +/- 5% before the operation to 62% +/- 33% at 31 +/- 8 days after the operation, 92% +/- 15% at 3.3 +/- 0.6 months after the operation, and 85% +/- 18% at 1.1 +/- 0.2 years after the operation. The control group showed no change in panel reactive antibodies, with a level of 1.6% +/- 1% before the operation, 3.2% +/- 1% 28 +/- 5 days after the operation, and 1.7% +/- 1% 2.7 +/- 0.3 months after the operation. Class II antibodies (anti-HLA-DR/DQ) rose to 49% +/- 35% at 30 +/- 8 days and 70% +/- 26% at 3.3 +/- 0.6 months after the operation. CONCLUSIONS: Cryopreserved allograft material induces a marked response that involves both class I and class II anti-HLA antibodies within 3 months after operation in children. This alloantibody response may represent a form of "rejection," may have implications for those who require subsequent cardiac transplantation, and may play a role in early allograft failure.

Left heart hypoplasia and neonatal aortic arch obstruction: is the Rhodes left ventricular adequacy score applicable?

OBJECTIVE: Although the influence of small left heart structures on outcome of a biventricular repair in neonatal critical aortic stenosis is well documented, little is known about its effect in neonates with aortic arch obstruction and coarctation. The purpose of this study was to evaluate the influence of small left heart structures on early and late results of repair and the ability to achieve a biventricular repair in neonates with coarctation and aortic arch obstruction. PATIENTS: Neonates included in this study had a left ventricular adequacy score (as proposed by Rhodes and associates for critical aortic stenosis) that would have predicted a need for a univentricular (Norwood) repair. All were ductus dependent but had antegrade ascending aortic flow and a small but nonstenotic aortic valve (<30 mm Hg gradient). Twenty neonates aged 10 +/- 9 days were identified for the study with weights averaging 3. 1 +/- 0.6 kg. Selected left heart measurements obtained by preoperative echocardiography included the following: aortic anulus 5.3 +/- 0.3 mm, mitral anulus 8.4 +/- 1.0 mm, transverse aortic arch 3.4 +/- 0.6 mm, and left ventricular volume 25 +/- 4 mL/m2. All patients underwent coarctation repair by resection and extended end-to-end anastomosis to enlarge the transverse arch as needed. Three patients underwent simultaneous pulmonary artery banding because of a hemodynamically significant ventricular septal defect. These 3 patients have subsequently had their defects successfully closed without mortality. RESULTS: There were no early or late deaths at a follow-up of 38 +/- 16 months after the operation. Three patients (3/20, 15%) have had to undergo reintervention with balloon aortoplasty because of recurrent coarctation (gradient > 20 mm Hg) in 2 and resection of subaortic stenosis in 1. Late follow-up in the remaining patients reveals 1 with moderate subaortic stenosis (gradient = 43 mm Hg), 2 with mild aortic stenosis (gradient < 30 mm Hg), and 2 with mild to moderate mitral stenosis. At late follow-up, 16 patients (16/20, 80%) are completely free of symptoms and 4 (4/20, 20%) have mild residual symptoms. CONCLUSIONS: Biventricular physiology can be successfully achieved in neonates with small left heart structures and aortic arch obstruction with minimal mortality and excellent late functional results. Standard echocardiographic measurements used to predict the need for a univentricular repair in critical aortic stenosis are not valid for the neonate with aortic arch obstruction.

Relaxation and imagery techniques without sedation during right ventricular endomyocardial biopsy in pediatric heart transplant patients.

Routine endomyocardial biopsies after heart transplantation can be performed in pediatric patients with the right internal jugular venous approach. To minimize hospital time, limit disruption of daily activities, and eliminate the need for sedation, biopsies in patients older than 7 years of age were done with relaxation and imagery techniques. No complications occurred with this method, and all patients tolerated the procedure well.

Effects of T cells on platelet-derived growth factor-like protein secretion from endothelial cells.

The cause of accelerated graft arteriosclerosis after heart transplantation is unknown. To examine whether the interactions of T cells and endothelial cells (ECs) could contribute to the cause of this phenomenon, T cells were co-incubated with human umbilical artery endothelial cells (HUAEC) and human vein endothelial cells (HUVEC) and the resulting conditioned medium supernatant was assayed for the presence of platelet-derived growth factor (PDGF)-like protein. PDGF-like protein secretion was significantly greater from HUAECs co-incubated with T cells at T-cell/HUAEC ratios of 30:1 (6.9 +/- 1.1 fmol/10(6) ECs) and 10:1 (6.0 +/- 1.1 fmol/10(6) ECs) than the combined background secretion from HUAECs and T cells incubated separately (3.6 +/- 0.8 fmol/10(6) ECs) (p less than 0.05). PDGF-like protein secretion above background levels from HUAECs was significantly greater, however, than from HUVECs co-incubated with T cells at T-cell/HUVEC ratios of 30:1 (1.0 +/- 0.4 fmol/10(6) ECs) and 10:1 (0.75 +/- 0.36 fmol/10(6) ECs) (p less than 0.05). In four experiments, preincubation of HUAECs with gamma-interferon induced HLA-DR antigen expression but actually caused a decrease in T-cell-induced PDGF-like protein secretion above background levels (3.0 +/- 0.6 fmol/10(6) ECs) when compared to nonstimulated HUAECs (4.0 +/- 0.4 fmol/10(6) ECs; p less than 0.05). PDGF-like protein secretion was minimal at 1 hour and increased over time to a maximum at 24 hours. The conclusion is that T cells are capable of inducing secretion of a very potent mitogen, PDGF-like protein, from endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital heart disease with ductal-dependent systemic perfusion: Doppler ultrasonography flow velocities are altered by changes in the fraction of inspired oxygen.

BACKGROUND: An unfavorable balance in systemic and pulmonary perfusion may occur in neonates with ductal-dependent systemic perfusion while being treated with prostaglandin E1 before surgical palliation or transplantation. At our institution, we adjust the fraction of inspired oxygen, with supplemental nitrogen if needed, to control pulmonary vascular tone and maintain systemic oxygen saturations near 75%. METHODS: We performed a noninvasive Doppler ultrasound study in 10 patients to determine whether velocity time integrals in the descending aorta and middle cerebral arteries and the peak velocity at the foramen ovale were acutely altered by changes in the fraction of inspired oxygen. Measurements were performed after 10- to 15-minute intervals of breathing 14% to 19%, 21%, and 35% oxygen. RESULTS: Antegrade descending aortic velocity time integrals did not change significantly when these patients breathed different amounts of oxygen; however, the retrograde velocity time integral in the descending aorta and the peak velocity of left-to-right shunt at the foramen ovale increased with increasing amounts of inspired oxygen. The ratio of antegrade to retrograde velocity time integrals in the descending aorta was greater with supplemental nitrogen than with supplemental oxygen. Middle cerebral arterial velocity time integrals were not significantly greater with supplemental nitrogen than with supplemental oxygen (p = 0.061). CONCLUSIONS: Systemic and interatrial Doppler velocities are acutely influenced by the fraction of inspired oxygen in neonates with ductal-dependent systemic perfusion.

Myocardial apoptosis in a heterotopic murine heart transplantation model of chronic rejection and graft vasculopathy.

BACKGROUND: Apoptosis has been implicated in myocardial reperfusion injury and in experimental transplantation rejection. One mechanism of apoptosis is through the interaction of the cell-surface Fas receptor on target cells and the Fas ligand that is expressed on cytotoxic T cells. The purpose of this study was to look for evidence of myocardial Fas receptor, Fas ligand, and apoptosis in a murine heterotopic heart transplantation model of chronic rejection/graft vasculopathy. METHODS: Using the nick-end labeling technique, we examined a murine heterotopic heart transplantation model of chronic rejection/graft vasculopathy (strain B10.A to B10.BR) histologically for evidence of DNA fragmentation. MRNA for the Fas receptor, Fas ligand, and beta-actin was detected with reverse transcription-polymerase chain reaction. RESULTS: Hearts harvested after 30 and 60 days showed an intimal index of the allografts (0.5 +/- 0.1) (mean +/- standard error) that was at least five times more than syngeneic grafts and native (nontransplanted) hearts (p < 0.01). In situ nick end-labeling of partially degraded DNA with terminal deoxynucleotydil transferase showed an increase in apoptotic cells in allografts and syngeneic grafts compared with native hearts. Reverse transcription-polymerase chain reaction detected equal myocardial RNA signal intensity of Fas receptor and beta-actin in allografts, syngeneic grafts, and native hearts. In contrast, allografts showed a strong signal for the Fas ligand mRNA, a signal not seen in syngeneic grafts or native hearts. CONCLUSIONS: Apoptosis is occurring in both allografts and syngeneic grafts in this murine model of chronic rejection/graft vasculopathy, although distinct mechanisms may be involved.

Intra-aortic balloon pumping in children with dilated cardiomyopathy as a bridge to transplantation.

Children with dilated cardiomyopathy awaiting transplantation who fail maximal pharmacologic therapy may benefit from intra-aortic balloon pumping. Between July 1993 and August 1999, a total of 4 children with dilated cardiomyopathy underwent pre-transplant balloon pumping for 6.0 +/- 5.8 (1 to 12) days. One child (pumped for 12 days) died awaiting transplant, and the remaining 3 were successfully transplanted. Intra-aortic balloon pumping timed precisely with M-mode echocardiographic markers offers a relatively simple and safe intermediate level of mechanical support for children with dilated cardiomyopathy who fail pharmacologic support.