Abstract Background Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or ...with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children. Methods and Results According to diagnoses from the National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups ( P = .035). Time to listing for cardiac transplantation significantly differed by phenotype ( P < .001), as did time to transplantation ( P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval CI 0.78–23.3) for HCM, 6.35 (95% CI 1.52–26.6) for DCM, and 5.66 (95% CI 1.04–30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis. Conclusions LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management.
Objectives This study sought to determine the incidence and predictors of recovery of normal echocardiographic function among children with idiopathic dilated cardiomyopathy (DCM). Background Most ...children with idiopathic DCM have poor outcomes; however, some improve. Methods We studied children <18 years of age from the Pediatric Cardiomyopathy Registry who had both depressed left ventricular (LV) function (fractional shortening or ejection fraction z- score <–2) and LV dilation (end-diastolic dimension LVEDD z- score >2) at diagnosis and who had at least 1 follow-up echocardiogram 30 days to 2 years from the initial echocardiogram. We estimated the cumulative incidence and predictors of normalization. Results Among 868 children who met the inclusion criteria, 741 (85%) had both echocardiograms. At 2 years, 22% had recovered normal LV function and size; 51% had died or undergone heart transplantation (median, 3.2 months), and 27% had persistently abnormal echocardiograms. Younger age (hazard ratio HR: 0.92; 95% confidence interval CI: 0.88 to 0.97) and lower LVEDD z- score (HR: 0.78; 95% CI: 0.70 to 0.87) independently predicted normalization. Nine children (9%) with normal LV function and size within 2 years of diagnosis later underwent heart transplantation or died. Conclusions Despite marked LV dilation and depressed function initially, children with idiopathic DCM can recover normal LV size and function, particularly those younger and with less LV dilation at diagnosis. Investigations related to predictors of recovery, such as genetic associations, serum markers, and the impact of medical therapy or ventricular unloading with assist devices are important next steps. Longer follow-up after normalization is warranted as cardiac failure can recur. (Pediatric Cardiomyopathy Registry; NCT00005391 )
Objective Pulmonary venous obstruction (PVO) is an important cause of late mortality in total anomalous pulmonary venous connection (TAPVC). We aimed to describe current practices for the management ...of postoperative PVO and the efficacy of the different interventional procedures. Methods We conducted a retrospective international collaborative population-based study involving 19 pediatric cardiac centers in the United Kingdom, Ireland, and Sweden. Patients with TAPVC born between January 1, 1998, and December 31, 2004, were identified. Patients with functionally univentricular circulation or atrial isomerism were excluded. All available data and images were reviewed. Results Of 406 patients undergoing repair of TAPVC, 71 (17.5%) had postoperative PVO. The diagnosis was made within 6 months of surgery in 59 (83%) of the 71 patients. In 12, serial imaging documented change in appearance of the pulmonary veins. Good-sized pulmonary veins can progress to diffusely small veins and rarely atresia. Patients presenting after 6 months had less severe disease; all are alive at most recent follow-up. Fifty-six (13.8%) of 406 patients underwent intervention for postoperative PVO: 44 had surgical treatment and 12 had an initial catheter intervention. One half underwent 1 or more reinterventions. Three-year survival for patients with postoperative PVO was 58.7% (95% confidence intervals, 46.2%-69.2%) with a trend that those having a surgical strategy did better ( P = .083). Risk factors for death included earlier presentation after TAPVC repair, diffusely small pulmonary veins at presentation of postoperative PVO, and an increased number of lung segments affected by obstruction. Conclusions Postoperative PVO tends to appear in the first 6 months after TAPVC repair and can be progressive. Early intervention for PVO may be indicated before irreversible secondary changes occur.
Cardiomyopathy is a serious disorder of the heart muscle and, although rare, is a common cause of heart failure in children and the most common cause for heart transplantation in children older than ...1 year of age. Funded by the National Heart Lung and Blood Institute since 1994, the Pediatric Cardiomyopathy Registry (PCMR) has followed more than 3500 North American children with cardiomyopathy. Early analyses determined estimates for the incidence of pediatric cardiomyopathy (1.13 cases per 100,000 children per year), risk factors for cardiomyopathy (age <1 year, male sex, black race, and living in New England as opposed to the central southwestern states), the prevalence of heart failure at diagnosis (6%-84% depending on cause), and 10-year survival (29%-94% depending on cause). More recent analyses explored cause-specific functional status, survival and transplant outcomes, and risk factors in greater detail. For many topics these analyses are based on the largest and best-documented samples of children with disease such as the muscular dystrophies, mitochondrial disorders, and Noonan syndrome. Data from the PCMR continue to provide valuable information that guides clinical management and the use of life-saving therapies, such as cardiac transplantation and approaches to treating heart failure, and prepares children, their families, and their caregivers to deal with this serious condition.
Allosensitization is associated with inferior waitlist outcomes in pediatric heart transplant candidates, presumably because of the requirement for a negative prospective crossmatch. However, there ...are no reports of heart transplant candidate outcomes according to prospective crossmatch requirements.
We analyzed data on all children listed for isolated heart transplantation from 1995 to 2009 in the USA according to prospective crossmatch requirement (PXMR). Primary objectives were to describe the prevalence of PXMR at and during listing and to compare waitlist and post-transplant survival for patients based on PXMR. Patients with a PXMR during listing include those with a PXMR at the time of listing as well as those who were designated by the listing center as needing a prospective crossmatch at some point after being placed onto the waitlist.
Among 6,343 listed children, 7.7% had a requirement for a prospective crossmatch at the time of listing and 11.8% had a requirement for a prospective crossmatch during listing. After controlling for risk factors associated with inferior survival, PXMR at listing was associated with increased waitlist mortality (HR 1.32, 95% CI 1.10 to 1.56; p = 0.003). Recipients with a PXMR during listing more commonly had a positive DSXM (22.1% vs 10.3%, p < 0.0001), as did recipients who carried a PXMR throughout listing (21.7% vs 11.3%, p = 0.004). However, there was no significant difference in post-transplant survival on the basis of a PXMR during listing (HR 1.04, 95% CI 0.87 to 1.25; p = 0.67). Nearly 30% of recipients with a PXMR during listing had a peak pre-transplant PRA ≤ 10%.
PXMR increases the likelihood of death while awaiting, but not after, pediatric heart transplantation. Further study is necessary to understand how PXMR is applied, and changes, after listing for pediatric heart transplantation.
Mycophenolate mofetil (MMF) is an effective and commonly used immunosuppressant but has frequent adverse events. Genetic polymorphisms may contribute to variability in MMF efficacy and related ...complications. In this study we explore the distribution frequencies of common single nucleotide polymorphisms (SNPs) of IMPDH1, IMPDH2 and ABCC2 and investigate whether these SNPs influence MMF adverse events in 59 pediatric heart recipients.
Genotypes were assessed by TaqMan analysis of: ABCC2 rs717620; IMPDH2 rs11706052; and IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294 and rs2228075. Gastrointestinal (GI) intolerance was defined as diarrhea, vomiting, nausea or abdominal pain requiring dose-holding for >48 hours or MMF discontinuation. Bone marrow toxicity was evaluated using Common Terminology Criteria for Adverse Events Version 3 (CTCAE).
GI intolerance occurred in 21 patients, and 21 had bone marrow toxicity. The ABCC2 rs717620 A variant was significantly associated with GI intolerance leading to drug discontinuation (p < 0.001); the IMPDH1 rs2278294 A variant and rs2228075 A variant were also associated with greater GI intolerance (p = 0.029 and p = 0.002, respectively). The IMPDH2 rs11706052 G variant was associated with more frequent neutropenia requiring dose-holding (p = 0.046).
In this small sample of pediatric heart transplant patients receiving MMF, ABCC2, IMPDH1 and IMPDH2 SNPs were associated with MMF GI intolerance and bone marrow toxicity. Thus, genetic polymorphisms may directly influence MMF adverse events.
Little is known about the effect of pre-transplant alloantibody in the pediatric cardiac transplant population.
All cardiac listings (n = 298) at Children's Hospital of Pittsburgh from January 1990 ...through February 2006 were reviewed to determine the impact of allosensitization on transplantation outcomes. Analysis focused on: (1) wait list outcomes; (2) survival from the time of listing, regardless of subsequent transplantation; (3) post-transplant graft and patient survival; and (4) post-transplant freedom from graft vasculopathy. Institutional policy required a negative, prospective crossmatch for candidates with panel-reactive antibody >20%.
Alloantibody data were available for 252 (85%) listings. Median time to transplantation was greater for sensitized vs non-sensitized subjects (2.7 months vs 1.3 months; p = 0.02). At 1 year after listing, sensitized subjects had a higher incidence of death (22% vs 8.4%; p = 0.055). Survival at all time-points after listing (regardless of transplantation) was worse for sensitized subjects (p = 0.04). Although no statistically significant differences in post-transplant graft or patient survival were noted, pre-transplant allosensitization was associated with decreased freedom from graft vasculopathy (hazard ratio HR 2.76, 95% confidence interval CI 1.18 to 6.45; p = 0.019).
A policy requiring a negative, prospective crossmatch for highly sensitized candidates is associated with longer wait list time and higher mortality after listing. The development of graft vasculopathy appears to be influenced by the presence of pre-transplant alloantibody.
C4d assessment of endomyocardial biopsies (EMBs) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether ...or not to assess all patients routinely and with what frequency/duration. In this study we sought to evaluate the utility of routine C4d immunostaining in the first year after pediatric and young adult HTx.
We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse capillary staining (≥ 2(+)) was present. Rare/focal capillary staining or absence of staining was considered negative.
Twenty-six of 406 first-year EMBs (6%) were C4d(+) in 6 (12%) patients. Sixty-five percent of all C4d(+) EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA) ≥ 4,000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA ≥ 4,000 MFI and/or a positive DSXM were C4d(+) compared with only 1 of 41 without (50% vs 2%; p = 0.001).
In the first year after HTx, C4d(+) occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. Although our data suggest that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA ≥ 4,000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance.
Depending on the part of the world one lives in, restrictive cardiomyopathy is either one of the rarest forms of cardiomyopathy in childhood, with no cause usually identified, or it is secondary to a ...poorly understood disease, endomyocardial fibrosis, that is endemic in some populations. Regardless of the underlying cause, the outcome is poor once symptoms develop. This article reviews the definitions, epidemiology, etiologies, genetics, "overlap" phenotypes, clinical presentation, diagnostic evaluation, outcome, and management of pediatric patients with restrictive cardiomyopathy.
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