Neda F. Mulla

Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)–generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction (∼65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.

Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results.

BACKGROUND Hypoplastic left heart syndrome is a lethal malformation. For the last 10 years, orthotopic cardiac transplantation has been our preferred treatment for infants with hypoplastic left heart syndrome. METHODS One hundred seventy-six infants with hypoplastic left heart syndrome were entered into a cardiac transplant protocol between November 1985 and November 1995. Interventional procedures to stent the ductus arteriosus or enlarge the interatrial communication were performed in 8 and 35 patients, respectively. Thirty-four patients (19%) died during the waiting period, and 142 infants underwent cardiac transplantation. Age at cardiac transplantation ranged from 1.5 hours to 6 months (median, 29 days). The majority of grafts were oversized, and the median graft ischemic time was 273 minutes (range, 60 to 576 minutes). The implantation procedure used a period of hypothermic circulatory arrest ranging from 23 to 110 minutes (median, 53 minutes). Repair of other significant defects included interrupted aortic arch and total or partial anomalous pulmonary venous connection. RESULTS There were 13 early and 22 late deaths. Patient actuarial survival at 1 month and at 1, 5 and 7 years was 91%, 84%, 76%, and 70% respectively. Half of the late deaths were due to rejection. Severe graft vasculopathy was confirmed in 8 patients. Retransplantation was performed in 5 patients for graft vasculopathy 4 and rejection 1. Lymphoblastic leukemia developed in 1 patient 3 years after cardiac transplantation. CONCLUSIONS Cardiac transplantation can be performed in infants with hypoplastic left heart syndrome with good operative and intermediate-term results. Improved survival can be achieved with increased donor availability, better management of rejection, and control of graft vasculopathy.

Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children

OBJECTIVES The purpose of this study was to determine the feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography (DSE) for evaluating posttransplant coronary artery disease (TxCAD) in children, and to determine the frequency of selected cardiac events after normal or abnormal DSE. BACKGROUND Posttransplant coronary artery disease is the most common cause of graft loss (late death or retransplantation) after cardiac transplantation (CTx) in children. Coronary angiography, routinely performed to screen for TxCAD, is an invasive procedure with limited sensitivity. The efficacy of DSE for detecting atherosclerotic coronary artery disease is established, but is unknown in children after CTx. METHODS Of the 78 children (median age 5.7 years, range 3 to 18) entered into the study, 72 (92%) underwent diagnostic DSE by means of a standard protocol, 4.6 +/- 1.9 years after CTx. The results of coronary angiography performed in 70 patients were compared with DSE findings. After DSE, subjects were monitored for TxCAD-related cardiac events, including death, retransplantation and new angiographic diagnosis of TxCAD. RESULTS No major complications occurred. Minor complications, most often hypertension, occurred in 11% of the 72 subjects. The sensitivity and specificity of DSE were 72% and 80%, respectively, when compared with coronary angiography. At follow-up (21 +/- 8 months), TxCAD-related cardiac events occurred in 2 of 50 children (4%) with negative DSE, versus 6 of 22 children (27%) with positive DSE (p < 0.01). CONCLUSIONS DSE is a feasible, safe and accurate screening method for TxCAD in children. Positive DSE identifies patients at increased risk of TxCAD-related cardiac events. Negative DSE predicts short-term freedom from such events.

Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy

Surgical mortality is high in children with visceral heterotaxy (VH), particularly if atrioventricular valve insufficiency, ventricular dysfunction, or aortic atresia is present. This study reviews the outcome of cardiac transplantation (CT) in infants and children with VH and congenital heart disease who are at high risk for standard palliative or corrective surgery. We reviewed CT outcomes in 29 children with VH, congenital heart disease, atrioventricular valve insufficiency, ventricular dysfunction, and/or aortic atresia. Median age at CT was 3.1 years. Cardiac surgery had been performed in 20 patients (69%) before CT. Follow-up since CT has been 8.5 ± 2.2 years. Outcomes were compared with 45 children who underwent transplantation for dilated cardiomyopathy. Actuarial graft survival in the VH group at 30 days and 1, 5, and 10 years was 100%, 86%, 68%, and 50%, respectively, compared with 100%, 96%, 83%, and 68% in children who underwent transplantation for dilated cardiomyopathy (p = 0.12). Splenic status, cardiac position, age at CT, number of prior cardiac surgeries, or systemic venous anomalies were not predictors of mortality after CT. Cardiopulmonary bypass and graft ischemic times were longer in the VH group; time on the ventilator after CT, length of hospitalization, and rejection, infection, post-transplant lymphoproliferative disease, and transplant coronary artery disease rates were equal. Thus, CT is a viable alternative therapy for high-risk patients with VH, possibly offering improved survival over standard surgical management.

Decreased Exercise Performance with Age in Children with Hypoplastic Left Heart Syndrome

OBJECTIVE Children born with hypoplastic left heart syndrome (HLHS) may experience cardiac dysfunction after staged surgery or transplantation, which may worsen with age. We examined the hypothesis that exercise testing can address cardiovascular capacity and suggest interventions to improve quality of life. STUDY DESIGN Children with HLHS > or = 8 years old performed treadmill or bicycle ergometric testing at 4 centers. Results were compared with norms for age and sex. RESULTS Of the 42 participants, the mean age was 12.9 years (range, 8.5-17.0 years), 64% were boys, 20 had staged surgery, and 34 completed metabolic assessment. The percent of predicted maximal oxygen uptake (mVO2) was higher in younger children. Children aged 8 to 12 years achieved 70% of predicted mVO2; children aged 13 to 17 years achieved 60% of predicted mVO2 (P = .02). The percent of predicted peak heart rate trended higher in younger patients (83% versus 75%, P = .07). Electrocardiographic changes were more common in older children. In treadmill testing, patients who had a transplant had better exercise performance than patients who underwent staged surgery in percent of predicted exercise time (82% versus 54%, P < .0001) and peak rate-pressure product (241 x 10(3) versus 195 x 10(3), P = .02). The percent of predicted mVO2 did not differ between patients who had a transplant (66%) and patients who underwent staged surgery (61%, P = .25). CONCLUSION Children with HLHS showed considerable age-related decline in exercise performance, regardless of surgical strategy.

Moderate acute rejection detected during annual catheterization in pediatric heart transplant recipients.

BACKGROUND Acute rejection commonly occurs within the first year after heart transplantation, and then decreases in frequency with time. Recently, the long-term utility of endomyocardial biopsy during routine annual catheterization has been questioned. The purpose of this study was to retrospectively review the prevalence of biopsy-proven rejection during routine annual catheterization in our patient population, determine whether biopsies late after transplant are useful, and identify factors that correlate with late unsuspected rejection. METHODS Biopsy results from the annual catheterization were evaluated from 1986 to August 2000. The prevalence of moderate rejection was evaluated and compared with the patients immunosuppressive regimen; the prevalence of late rejection; and how late rejection correlated with recipient age, number of first-year rejections and presence of sub-therapeutic cyclosporine. RESULTS A total of 1108 biopsies were performed in 269 children with a mean follow-up of 5 +/- 3 years (median 5 years, range 1 to 11 years). Three-drug immunosuppressive therapy, including steroids, was used in 93 patients. There was a persistent 8% to 10% prevalence of moderate rejection at up to 10 years post-transplantation. Moderate rejection was more likely in patients: (1). on 3-drug immunosuppressive therapy; (2). with a recipient age >1 year; and (3). with a relatively lower cyclosporine level. CONCLUSIONS These data suggest that continued surveillance of pediatric transplant patients for acute rejection is indicated for long-term follow-up.

Outcome of infants with hypoplastic left heart syndrome who undergo atrial septostomy before heart transplantation.

This study evaluated the procedural and long-term outcome of infants who underwent atrial septostomy while awaiting transplant. The results suggest that septostomy improved outcome in these patients although infants needing a transseptal perforation were at higher risk.

VENTRICULAR REMODELING FOLLOWING INFANT-PEDIATRIC CARDIAC TRANSPLANTATION: Does Age at Transplantation or Size Disparity Matter?1, 2

Early left ventricular (LV) remodeling following pediatric cardiac transplantation has not been described. To identify patterns and determinants of change in left ventricular mass and volume posttransplant, we studied 125 consecutive children who underwent cardiac transplantation between January 1, 1989 and July 31, 1993. Two-dimensional imaging-directed M-mode echocardiograms were studied weekly until 26 weeks post-transplant. LV mass and volume (indexed to BSA1.5) were measured. LV mass index increased until 3 weeks post-transplant, and then decreased. The mean decrement in LV mass index after 8 weeks post-transplant (relative to baseline) was significantly larger in patients with donor-recipient weight ratio > 1.5 compared with patients with donor-recipient weight ratio < or = 1.5 (-2.2 g/m3 compared with 33.4 g/m3, respectively, P < 0.01). Multiple linear regression was performed employing donor-recipient weight ratio, time since transplantation, ischemic time, and age at transplant as prognostic variables. Donor-recipient weight ratio (P < 0.0001), time since transplant (P < 0.01), and age at transplant (P = 0.02) were identified as independent predictors of change in LV mass index. Donor-recipient weight ratio (P = 0.001) and time since transplantation (P = 0.02) were independent predictors of change in LV volume index. There was an interaction between donor-recipient weight ratio and time since transplantation, suggesting that donor-recipient weight ratio has an independent effect as well as a time-dependent effect on change in LV mass and volume indices. LV mass and volume indices increased early posttransplant and then decreased; this pattern was temporally predictable, and dependent on donor-recipient weight ratio and age at transplant.

Fate of polytetrafluoroethylene monocusp pulmonary valves in an animal model.

Creation of a competent pulmonary monocusp valve facilitates transition from pressure to volume overload following right ventricular outflow tract reconstruction. To determine intermediate-term results and performance of the different types of polytetrafluoroethylene membrane used to construct monocusp valves and transannular patches, 12 infant lambs underwent excision of the native pulmonary valve and insertion of a monocusp valve and transannular patch made from one of 4 types of membrane. Echocardiography was performed after 3, 6, 9, and 12 months, and cardiac catheterization was carried out prior to animal sacrifice at 6 (n = 4) or 12 (n = 8) months. There was no postoperative morbidity or mortality. On echocardiography, 6 valves were mobile (50%), 4 had diminished mobility (33%), and 2 were fixed (17%) prior to sacrifice. At catheterization, mild, moderate, and severe pulmonary regurgitation was observed in 4 valves each (33%), with no stenosis. Right ventricular outflow tract reconstruction with polytetrafluoroethylene monocusp valves can be safely accomplished with good early competence, variable degrees of late insufficiency, and no stenosis. Compared to an open microstructure, the closed polytetrafluoroethylene microstructure showed a milder fibroinflammatory reaction and fewer foci of microcalcification, with sparing of the free edge of the monocusp; this correlated with better intermediate-term hemodynamic performance.

Posttransplant recoarctation of the aorta: a twelve year experience

OBJECTIVES This study was undertaken to investigate the incidence of posttransplant recoarctation of the aorta, delineate the mode of presentation, identify risk factors that predict recoarctation and examine the results of intervention for posttransplant recoarctation. BACKGROUND Patients with aortic arch hypoplasia require extended arch reconstruction at transplant, with an inherent possibility of subsequent recoarctation of the aorta. METHODS This was a retrospective review of all children (age <18 years) who underwent cardiac transplantation over a 10-year period. Collected data included pretransplant diagnosis, details of the transplant procedure and posttransplant data including development of recoarctation of the aorta, interventions for recoarctation and the most recent follow-up assessment of the aortic arch. RESULTS Two hundred eighty-eight transplants were performed on 279 children (follow-up = 1,075 patient-years; range 0 to 133 months, median 43.7). Thirty-two of 152 patients (21%) who underwent extended aortic arch reconstruction subsequently developed recoarctation. All but one patient developed recoarctation within 2 years after transplant; 87% were hypertensive at presentation. Of 30 patients who underwent intervention for recoarctation (balloon angioplasty [n = 26] and surgical repair of recoarctation [n = 4]), 26 (87%) have remained recurrence-free (follow-up = 133 patient-years; range 8 to 106 months, median 47). CONCLUSIONS The high frequency of recoarctation after cardiac transplantation with extended aortic arch reconstruction mandates serial echocardiographic evaluation of the aortic arch. Patients typically present with systemic hypertension within the first two years after transplantation. Balloon angioplasty is a safe, effective and durable method of treatment.