Driscoll, David J.

Abstract For cardiac transplantation in infants, T cells are depleted and the thymus is removed. These manipulations should cause profound defects in the T cell compartment. To test this concept, 20 subjects who underwent cardiac transplantation in infancy and healthy age-matched subjects were studied. The number of T cells in the blood was nearly normal in all subjects 1–10 years after surgery. However, newly generated T cells were undetectable in 10 recipients and 10-fold less than controls in 10, suggesting absence of thymic function. TCRβ chain diversity, measured by a novel technique, was ∼100-fold lower than controls. T cell function, deduced from levels of human herpesvirus 7 and response to hepatitis B immunization, were notably impaired. Yet cardiac transplant recipients were generally free of opportunistic infections. Our findings demonstrate a novel approach to measuring lymphocyte diversity and suggest that understanding how these subjects resist infection could yield important insights into immune fitness.

AbstractSirolimus is used in heart transplant patients with CAV and CNI‐induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus‐based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI‐free sirolimus‐based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI‐induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1–21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow‐up was available for a mean of 2.5 yr after conversion (range 0.5–8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient‐year (total of five episodes), compared with 0.03 rejection episodes per patient‐year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow‐up (from 86 ± 37 mL/min to 130 ± 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI‐free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles.

AbstractPosterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

Background —The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. Methods and Results —The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (≥30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or ≥10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. Conclusions —Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

BACKGROUND The purpose of this study was to estimate survival and quality of outcome and assess factors associated with outcome for patients out 5 to 15 years from their Fontan operation. METHODS AND RESULTS We studied 352 patients who had the Fontan operation prior to 1985. The overall 1-, 5-, and 10-year survival was 77%, 70%, and 60%, respectively. The following factors were significantly associated with lower survival: univentricular heart or complex congenital anomalies other than tricuspid atresia, early calendar year of operation, heterotaxia syndromes, early age at operation, increased pulmonary artery pressure, atrioventricular valve dysfunction, and higher (worse) New York Heart Association class. Reoperations were necessary for 103 of the 352 patients. At least 20% of the survivors have or have had cardiac arrhythmias requiring antiarrhythmic medication or mechanical pacemaker insertion. Between 7% and 10% of the patients have had or had protein-losing enteropathy/hypoproteinemia. At 5 years postoperatively, 122 patients (34.7%) were alive with a better New York Heart Association functional classification than preoperatively. Fifty-eight patients (16.5%) were alive and in the same functional classification, but 126 (35.8%) died within the first 5 years or were in a worse functional classification. Thirty-nine patients were doing excellently and 29 patients poorly 5 years after the operation. Of the surviving patients, 43% can do as much exercise as their peers, whereas 3% are incapable of exercise. CONCLUSIONS To assure good functional long-term outcome in addition to survival, clinicians must exclude from selection for Fontan operation patients known to be at high risk for death or poor outcome.

The objective of this study was to assess growth patterns of hyperlipidemic children enrolled in a preventive cardiovascular health clinic. A retrospective chart review of hyperlipidemic children enrolled in the Mayo Clinic Cardiovascular Health Clinic for the Young was performed. All participants were counseled to eat an American Heart Association Step-One Diet and exercise regularly. Weight and height were measured every 3 months. Growth was assessed using attained heights and weights and body-mass index Z scores compared to standard distributions for North American children. Sixty-three patients (33 males and 30 females) were enrolled in the study. Mean age at clinic entrance was 7.8 ± 3.5 years (range: 2 to 16 years). We conclude that participation in a preventive health clinic is generally safe for hyperlipidemic children. However, medical management of hyperlipidemic children must include meticulous surveillance to detect the infrequent occurrence of excessive weight loss or weight stabilization resulting from inappropriate response to dietary counseling.

Background — Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results — We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Conclusions — Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.