Debra A. Dodd

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Calcineurin Inhibitor Treatment of Intravenous Immunoglobulin–Resistant Kawasaki Disease

OBJECTIVE To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies. STUDY DESIGN Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped. RESULTS Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA. CONCLUSION Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement.

Modified Norwood operation for hypoplastic left heart syndrome

BACKGROUND We examined early results in infants with hypoplastic left heart syndrome undergoing the Norwood operation with perioperative use of inhaled nitric oxide and application of extracorporeal membrane oxygenation. METHODS Medical records were reviewed retrospectively. RESULTS Between April 1997 and March 2001, 50 infants underwent a modified Norwood operation for hypoplastic left heart syndrome. Mean age at operation was 7.5 +/- 5.7 days, and mean weight was 3.1 +/- 0.5 kg. Five infants had a delayed operation because of sepsis. The mean diameter of the ascending aorta by echocardiography was 3.6 +/- 1.8 mm. Ductal cannulation was used to establish cardiopulmonary bypass in all patients. Mean circulatory arrest time was 39.4 +/- 4.8 minutes. The size of the pulmonary-systemic shunt was 3.0 mm in 6 infants, 3.5 mm in 37, and 4.0 mm in 7. Infants with persistent hypoxia (partial pressure of oxygen < 30 mm Hg) received nitric oxide after they were weaned from cardiopulmonary bypass. Extracorporeal membrane oxygenation was initiated in 8 infants in the pediatric intensive care unit primarily for low cardiac output and in 8 in the operating room because of the inability to separate them from cardiopulmonary bypass. The 30-day mortality rate was 22% (11 of 50 patients), and the hospital mortality rate was 32% (16 of 50 patients). Mean follow-up was 17 months. Ten patients (20%) underwent stage-two repair, with one operative death. One survivor had a Fontan procedure, and 2 underwent heart transplantation, with one death. CONCLUSIONS Early application of extracorporeal membrane oxygenation for hemodynamic instability and selective use of nitric oxide for persistent hypoxia in the immediate postoperative period may improve survival of patients with hypoplastic left heart syndrome. Renal failure requiring hemofiltration during extracorporeal membrane oxygenation (p < 0.05) and cardiopulmonary arrest in the pediatric intensive care unit (p < 0.05) were predictors of hospital mortality.

Fontan-associated protein-losing enteropathy and heart transplant: A Pediatric Heart Transplant Study analysis

BACKGROUND Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort. METHODS Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed. RESULTS Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p < 0.0001). There were no intergroup differences for post-HTx survival or times to the first infection or rejection. PLE was not independently associated with increased post-HTx mortality at any time point. CONCLUSIONS In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx.

Heart transplantation in children

Orthotopic cardiac transplantation has been performed in 15 consecutive neonates and children since 1987. Diagnoses include hypoplastic left heart syndrome (5 patients), critical aortic stenosis with small left ventricle (1 patient), complex cyanotic heart disease (6 patients), and cardiomyopathy (3 patients). Twelve patients survived operation and have been followed from 1 to 45 months. Patients less than 6 years of age are managed with cyclosporine +/- azathioprine; in older patients steroid weaning is attempted. Monitoring for rejection is performed with serial echocardiography in patients under 6 years of age; older patients undergo serial biopsies. Actuarial freedom from rejection was 26% 3 months after operation; 47% were free of infection 6 months after operation. There have been no late deaths. Actuarial survival at 3 years is 79%. Nine patients have undergone postoperative catheterization. Resting hemodynamics were normal in every patient. All long-term survivors are asymptomatic and fully active. It is concluded that cardiac transplantation in neonates and children is an effective treatment option for end-stage cardiomyopathy or otherwise incurable congenital heart disease. Long-term survivors have excellent potential for full rehabilitation.

Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients

Autoimmune and allergic diseases cause morbidity and diminished quality of life in pediatric organ transplant recipients. We hypothesize that younger age at transplantation and immunosuppression regimen play a role in the development of immune‐mediated disease following heart transplant. A single institution retrospective review identified all patients undergoing heart transplant at ≤18 yr of age from 1987 to 2010 who survived ≥1 yr. Using medical record and database review, patients were evaluated for development of autoimmune or severe allergic disease. Of 129 patients who met criteria, seven patients (5.4%) with autoimmune or severe atopic disease were identified. Immune‐mediated diseases included inflammatory bowel disease (n = 3), eosinophilic esophagitis/colitis (n = 4), and chronic bullous disease of childhood (n = 1). Patients <1 yr of age at transplant were at greater risk of developing autoimmune disease than patients 1–18 yr at transplant (OR = 9.3, 95% CI 1.1–79.2, p = 0.02). All affected patients underwent thymectomy at <1 yr of age (7/71 vs. 0/58, p = 0.02). In our experience, heart transplantation in infancy is associated with the development of immune‐mediated gastrointestinal and dermatologic diseases. Further study is needed to determine risk factors for the development of immune‐mediated disease to identify best practices to decrease incidence.

Variation in the use of surveillance endomyocardial biopsy among pediatric heart transplant centers over time

EMB is widely utilized for graft surveillance after HTx; however, there is significant variation in the frequency of surveillance EMB use during the first year post‐HTx. The aim of this study was to assess changes in the utilization of surveillance EMB over time among member institutions of PHTS. A survey of PHTS centers assessing the frequency of surveillance EMB use during the first year post‐HTx was conducted in 2006. The same survey was repeated in 2014 to assess changes in practice over time. The number of EMB in infants ranged from 0 to 9 and in adolescents 0 to 16. The number of EMB decreased or remained unchanged in the majority of centers. Fewer EMB are performed in infants compared to adolescents and this practice did not change over time. There was a significant decrease in surveillance EMB use in adolescents (p = 0.012). International centers perform significantly fewer EMB in adolescents when compared to centers within the United States (p = 0.006). There continues to be significant variation in the utilization of surveillance EMB, with a shift toward less reliance on EMB for adolescents in the current era. Further research is necessary to determine the optimal frequency of invasive monitoring that reduces costs without compromising outcomes.

Routine Performance of Endomyocardial Biopsy Decreases the Incidence of Orthotopic Heart Transplant for Myocarditis

BACKGROUND In critically ill children presenting with dilated cardiomyopathy (DCM), the presence of myocarditis predicts an improved chance of myocardial recovery. Noninvasive differentiation of myocarditis from other causes of DCM is difficult. However, sensitivity of endomyocardial biopsy has been questioned. METHODS We reviewed clinical, echocardiographic, catheterization, and pathology data from all children admitted to the intensive care unit with DCM undergoing orthotopic heart transplantation since the inception of our transplant program in 1987 and all patients with definitively diagnosed myocarditis presenting since 1996. RESULTS Thirty-six patients with DCM underwent orthotopic heart transplantation. Cellular infiltrate was present in 3 of 36 (8.3%) explanted specimens. Pre-transplant biopsy was performed in 81%. No explanted heart demonstrated infiltrates after a negative biopsy. One biopsy was positive with negative explant histology after transplant 6 months later. No patient with biopsy-proven myocarditis died while listed for transplantation. Eleven additional patients with myocarditis did not undergo transplant. Ten have survived and experienced complete (n = 9) or near complete (n = 1) recovery of myocardial function. One patient died shortly after presentation from fulminant myocarditis. The 10 transplant-free survivors could not be easily distinguished from our transplant cohort by clinical features at presentation. CONCLUSION The incidence of cellular infiltrate in explanted hearts was significantly lower than that previously reported. Potentially, our aggressive myocarditis diagnostic protocol was useful in therapeutic stratification as a cohort of myocarditis patients avoided transplant and experienced complete recovery of myocardial function despite being difficult to distinguish clinically from our DCM transplant cohort at presentation.

Transient severe mitral and tricuspid regurgitation following blunt chest trauma

6. Sambas PN. Traumatic heart disease. Curr Probl Cardiol 1982;7:3. Maguire R. Interstitial aneurysm of the interauricular septum. Tram Path01 Sot Lond 1887:38:1SO. Orbison JL, Mostofi FK. Hematoma of the interatriai septum. AM HEART J 1956;51:636. Fyke FE, Seward JB, Edwards WD, et al. Primary cardiac tumors: experience with thirty consecutive patients since the introduction of two-dimensional echocardiography. J Am Co11 Cardiol 1985;5:1465. Mike11 FL, Asinger RW, Rourke T, Hodges M, Sharma B, Francis GS. Two-dimensional echocardiographic demonstration of left atria1 thrombi in patients with prosthetic mitral valves. Circulation 1979;60:1183.

Expanding the donor pool: regional variation in pediatric organ donation rates.

There are limited published data on pediatric organ donation rates. The aim of this study was to describe the trends in pediatric organ donation over time and to assess the regional variation in pediatric deceased organ donation. OPTN data were utilized to assess the trends in pediatric organ donation over time. The number of deceased pediatric organ donors was indexed using regional mortality data obtained from the National Center for Health Statistics and compared across UNOS regions and two different eras. The number of pediatric deceased organ donors has declined in the recent era, largely driven by fewer adolescent donors. For all age groups, there is significant regional variation in organ donation rates, with identifiable high‐ and low‐performing regions. Expansion of the donor pool may be possible by optimizing organ donation in regions demonstrating lower recruitment of pediatric donors. Using the region with the highest donation rate for each age group as the gold standard, we estimate a potential 24% increase in the number of donors if all regions performed comparably, equating to 215 new pediatric donors annually.