K.M. Molina

Predictors of Disease Progression in Pediatric Dilated Cardiomyopathy

Background—Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM. Methods and Results—The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using Cox proportional hazards modeling and classification and regression tree analysis. Of the 127 patients, 28 (22%) had disease progression during the 18-month follow-up. Multivariable analysis identified older age at diagnosis (hazard ratio=1.14 per year; P<0.001), larger left ventricular (LV) end-diastolic M-mode dimension z-score (hazard ratio=1.49; P<0.001), and lower septal peak systolic tissue Doppler velocity z-score (hazard ratio=0.81; P=0.01) as independent predictors of disease progression. Classification and regression tree analysis stratified patients at risk of disease progression with 89% sensitivity and 94% specificity based on LV end-diastolic M-mode dimension z-score ≥7.7, LV ejection fraction <39%, LV inflow propagation velocity (color M-mode) z-score <−0.28, and age at diagnosis ≥8.5 months. Conclusions—In children with chronic stable DCM, a combination of diagnosis after late infancy and echocardiographic parameters of larger LV size and systolic and diastolic function predicted disease progression. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123071.

ISHLT pathology antibody mediated rejection score correlates with increased risk of cardiovascular mortality: A retrospective validation analysis

BACKGROUND Antibody-mediated rejection (AMR) in cardiac transplant recipients is a serious form of rejection with adverse patient outcomes. The International Society of Heart and Lung Transplantation (ISHLT) has published a consensus schema for the pathologic diagnosis of various grades of antibody-mediated rejection (pathology antibody-mediated rejection [pAMR]). We sought to determine whether the ISHLT pAMR grading schema correlates with patient outcomes. METHODS Using our database, which contains a semi-quantitative scoring of all pathologic descriptors of pAMR, we retrospectively used these descriptors to convert the previous AMR categories to the current ISHLT pAMR categories. Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable, and cellular rejection (CR) values were included in a separate model. RESULTS There were 13,812 biopsies from 1,014 patients analyzed. The pAMR grades of pAMR1h, pAMR1i, and pAMR2 conferred comparable increased risk for CV mortality. Significantly increased risk of CV mortality was conferred by biopsies graded as severe AMR (pAMR3). CONCLUSIONS The new ISHLT pAMR grading schema identifies patients at increased risk of CV mortality, consistent with risks published from several programs before 2011. The current schema is validated by this analysis in a large biopsy database. Because pAMR1h, pAMR1i, and pAMR2 have similar CV risks associated with them, the threshold for a positive diagnosis of pAMR should be re-evaluated in future iterations of the ISHLT schema.

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations

BACKGROUND Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. METHODS The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. RESULTS Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. CONCLUSIONS MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

Impact of initial Norwood shunt type on young hypoplastic left heart syndrome patients listed for heart transplant: A multi-institutional study

BACKGROUND Pulmonary blood flow during Stage 1 (Norwood) palliation for hypoplastic left heart syndrome (HLHS) is achieved via modified Blalock-Taussig shunt (MBT) or right ventricle to pulmonary artery conduit (RVPA). Controversy exists regarding the differential impact of shunt type on outcome among those who require transplantation early in life. In this study we explored waitlist and post-transplant outcomes within this sub-population stratified by shunt type. METHODS Eligible patients were enrolled through the Pediatric Heart Transplant Study (PHTS) database. Patients included those listed for heart transplantation at 1 of 35 participating centers, all of whom were <6 years of age and with a diagnosis of HLHS (and variants) status post Stage 1 palliation with MBT or RVPA. Standard risk factors for death were analyzed using multivariable hazards modeling. RESULTS Between 2010 and 2013, 190 patients were identified. Compared with the RVPA group (n = 111), the MBT group (n = 79) was less likely to have undergone a Glenn palliation (41% vs 73%, p < 0.001), were younger at listing (median age 1.3 vs 1.8 years, p = 0.05), had lower median weight (7.9 vs 9.4 kg, p = 0.02), and were more likely to be mechanically ventilated at listing (35% vs 22%, p = 0.04). There were no significant differences in median waitlist time (1.7 vs 2.6 months, p = 0.2) or rate of transplantation (61% vs 60%, p = 1.0). Among waitlisted patients, 3-month survival was less for MBT compared with RVPA patients (74% vs 91%, p = 0.02). Patients who had not yet achieved Glenn palliation before listing had lower waitlist 3-month survival (76% vs 90%, p = 0.02). In MBT infants <1 year old, there was a trend toward improved survival in those with Glenn palliation compared to those without (100% vs 68%, p = 0.08). Early post-transplant mortality rates were similar between the RVPA and MBT groups (p = 0.4) with overall survival 84% at 1 year. CONCLUSIONS Among HLHS patients, the need for transplant before Glenn palliation is associated with poorer waitlist survival. Waitlist survival is poorer in the MBT group, with this difference driven by pre-Glenn MBT infants. Post-transplant outcomes were unaffected by shunt type.

Pulmonary artery resuscitation for isolated ductal origin of a pulmonary artery

OBJECTIVE Ductal origin of a pulmonary artery (DOPA) is commonly misdiagnosed as agenesis of a pulmonary artery (PA), which may result in inadequate treatment. The objective is to describe the results of resuscitation of unilateral DOPA. METHODS This study is a retrospective review of all patients with unilateral DOPA who underwent PA resuscitation at Texas Childrens Hospital from 1993 to 2012. Patients with other cardiac or contralateral lung anomalies were excluded. RESULTS Ten patients, median age 2 years (range, 3 days to 9 years), with unilateral DOPA were included. Symptoms were present in 6 patients. Cardiac catheterization was performed in all and showed a patent duct or a ductal stump in most patients and a small PA on wedge angiography of the pulmonary veins. Two patients underwent single-stage centralization. The other 8 underwent ductal stenting (n=2) or a systemic-to-PA shunt (n=6) as the first stage before centralization. The 2 patients with ductal stenting developed pulmonary edema. The 2 patients with a cryopreserved vein shunt developed early thrombosis requiring reintervention. Nine patients have undergone centralization. Six patients have required further interventional procedures. There have been no deaths. Symptoms and lung hypoplasia have improved in all patients. Median relative lung perfusion at follow-up was 26% (range, 12%-46%) with significant improvement in the size of the affected PA. CONCLUSIONS PA resuscitation is effective at restoring flow to the affected lung resulting in improved diameter of the PA, lung growth, and resolution of symptoms. PA resuscitation should be considered in all children with DOPA, including those beyond infancy.

When Lightning Strikes Twice in Pediatrics: Case Report and Review of Recurrent Myocarditis

In this article we highlight a unique, illustrative pediatric case of recurrent myocarditis and review the existing literature on the topic. Myocarditis is an important but incompletely understood cause of cardiac dysfunction. Children with fulminant myocarditis often require inotropic or mechanical circulatory support, and researchers in some studies suggest that up to 42% of children who die suddenly have evidence of myocarditis. Recurrent myocarditis is extremely rare, and the vast majority of reported cases involve adult patients. Pediatric providers who suspect a recurrence of myocarditis have limited evidence to guide patient management because the literature in this domain is sparse. Here we present a unique, illustrative pediatric case of recurrent myocarditis. A 14-year-old boy presented for the second time in 2 years with a clinical history strongly suggestive of myocarditis. Although myocarditis was suggested in the results of cardiac MRI, no pathogen was identified during his first presentation. During his second episode of myocarditis, parvovirus was confirmed by polymerase chain reaction testing of an endomyocardial specimen that also met Dallas criteria for myocarditis. With each presentation, he had decreased ventricular function that subsequently normalized. To the best of our knowledge, there are no reports of recurrent myocarditis in children in whom the diagnosis was confirmed by using MRI and/or biopsy data. Reviewing this distinctive case and the existing literature may help characterize this entity and raise awareness among care providers.

Cardiac allograft vasculopathy following fecal microbiota transplantation for recurrent C. difficile infection

We report the case of a 3‐year‐old male who developed recurrent Clostridium difficile infection after receiving an orthotopic heart transplant. Despite multiple courses of antibiotics, C. difficile infection was persistent and he underwent a fecal microbiota transplant. The patient responded with resolution of his diarrhea. However, within 2 months he developed severe mixed rejection with high circulating donor‐specific antibodies and significant coronary vasculopathy. Organ dysfunction led to the need for re‐transplantation. The patients postoperative course has since been complicated by pneumatosis intestinalis and recurrent C. difficile infection.

The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database

Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross‐match and the post‐transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA > 20%. Patients with a PRA > 20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross‐match determined by flow cytometric method (P < .001). A PRA > 50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era.

Reproducibility of Left Ventricular Dimension Versus Area Versus Volume Measurements in Pediatric Patients With Dilated CardiomyopathyCLINICAL PERSPECTIVE

Background— Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. Methods and Results— In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean)×100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements (P⩽0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements (P⩽0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences (P<0.001). Conclusions— In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Viral endomyocardial infection in the 1st year post transplant is associated with persistent inflammation in children who have undergone cardiac transplant.

BACKGROUND Viral genome in cardiac allograft has been associated with early graft loss in children who have undergone cardiac transplant from unknown mechanisms. METHODS This study is a retrospective review of children who have undergone cardiac transplant at a single institution from 1/2004 to 5/2008. Patients underwent cardiac catheterisations with endomyocardial biopsies to evaluate for rejection--graded on Texas Heart Institute scale--and the presence of virus by polymerase chain reaction. Patients with virus identified during the first year post transplant were compared at 1 year post transplant with virus-free patients. RESULTS The cohort comprised 59 patients, and the median age at transplant was 5.1 years. Viral genomes were isolated from 18 (31%) patients. The PCR + group had increased inflammation on endomyocardial biopsies, with a median score of 4 (ISHLT IR) versus 1 (ISHLT 1R) in the PCR--group (p = 0.014). The PCR + group had a similar cardiac index (median 3.7 ml/min/m(2)), pulmonary capillary wedge pressure (median 10 mmHg), and pulmonary vascular resistance index (median 1.7 U m(2)) comparatively. PCR + patients were more likely to have experienced an episode of rejection (p = 0.004). CONCLUSIONS Children who developed viral endomyocardial infections after a cardiac transplant have increased allograft inflammation compared with virus-free patients. However, the haemodynamic profile is similar between the groups. The ongoing subclinical inflammation may contribute to the early graft loss associated with these patients.