Steven J. Kindel

Pediatric cardiomyopathy: importance of genetic and metabolic evaluation.

BACKGROUND Cardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry identified familial, syndromic, or metabolic causes in 30% of children. However, these results predated clinical genetic testing. METHODS AND RESULTS We determined the prevalence of familial, syndromic, or metabolic causes in 83 consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006 to 2009. Seventy-six percent of probands (n = 63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n = 18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%; n = 7) and metabolic (26%; n = 11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%; n = 5) and metabolic (16%; n = 4) causes, but fewer familial cases (24%; n = 6) compared with HCM patients. CONCLUSIONS The cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in >35% of children with HCM or DCM. Identification of etiology is important for management, family-based risk assessment, and screening.

Current therapies for cardiac allograft vasculopathy in children.

Heart transplantation is an accepted therapy for end-stage heart disease in children and adults. Over the past 25 years, the perioperative and 1-year mortality has steadily improved, leading to an increased focus on midterm and late-term complications. Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss in children. The prevalence of disease increases steadily after transplantation from 5% at 2 years to 35% by 10 years according to multiple database analyses. Allograft vasculopathy is the end point of a complex interaction of stimuli including chronic rejection, endothelial dysfunction, infection, and traditional cardiac risk factors. While an increased understanding of risks associated to CAV has led to more aggressive surveillance approaches, the rates of CAV remain high and outcomes after diagnosis of CAV are very poor with up to 50% of children suffering graft loss or death within 2 years of diagnosis. In an attempt to combat the development and progression of CAV, multiple medical and interventional strategies have been utilized. Pharmacologic approaches have focused on the use of various immunosuppressants and adjuvant medications to combat inflammation and immune mediated graft injury. While randomized controlled trials are rare in pediatric heart transplant cohorts, sufficient adult data have been developed in both controlled and observational trials to provide a framework for the prevention and management of patients with CAV. However, none of these interventions have been shown to be effective in significantly prolonging graft survival and retransplantation remains the only reliable therapy for severe CAV.

Eosinophilic esophagitis in children following cardiac transplantation: association with post-transplant lymphoproliferative disorder and other transplant outcomes.

Although cardiac transplantation is life‐saving, morbidities from immunosuppression are significant. EoE is a complication of calcineurin inhibitors following liver transplant causing feeding intolerance, weight loss, vomiting, and dysphagia. There are limited reports of EoE following heart transplantation. We performed a retrospective single‐center review of pediatric cardiac transplant patients from 2000 to 2010. A case–control analysis of patients with and without EoE was performed evaluating heart transplantation outcomes such as rates of rejection, CAV, PTLD, and graft loss. Eighty‐six transplants were performed in 84 patients; 34 (40%) underwent diagnostic endoscopy, and 10 (12%) had EoE. Median time to diagnosis of EoE was 3.7 yr (IQR: 2.0–5.2). There were no differences in demographics or use of induction medications between patients with or without EoE. Patients with EoE had fewer episodes of treated rejection (1.0 vs. 2.5; p = 0.04). Four of 10 (40%) EoE patients had PTLD compared with only 2/24 (8%) of those without EoE (p = 0.048; OR 7.33 [95% CI: 1.1–50.2]). There were no differences in CAV or graft loss between groups. EoE should be considered as a cause of GI symptoms in children after cardiac transplantation and may be associated with fewer rejection episodes and increased rates of PTLD, thus representing a marker of over‐immunosuppression.

Haemodynamic profiles of children with end-stage heart failure

Aims To evaluate associations between haemodynamic profiles and symptoms, end-organ function and outcome in children listed for heart transplantation. Methods and results Children <18 years listed for heart transplant between 1993 and 2013 with cardiac catheterization data [pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and cardiac index (CI)] in the Pediatric Heart Transplant Study database were included. Outcomes were New York Heart Association (NYHA)/Ross classification, renal and hepatic dysfunction, and death or clinical deterioration while on waitlist. Among 1059 children analysed, median age was 6.9 years and 46% had dilated cardiomyopathy. Overall, 58% had congestion (PCWP >15 mmHg), 28% had severe congestion (PCWP >22 mmHg), and 22% low cardiac output (CI < 2.2 L/min/m2). Twenty-one per cent met the primary outcome of death (9%) or clinical deterioration (12%). In multivariable analysis, worse NYHA/Ross classification was associated with increased PCWP [odds ratio (OR) 1.03, 95% confidence interval (95% CI) 1.01-1.07, P = 0.01], renal dysfunction with increased RAP (OR 1.04, 95% CI 1.01-1.08, P = 0.007), and hepatic dysfunction with both increased PCWP (OR 1.03, 95% CI 1.01-1.06, P < 0.001) and increased RAP (OR 1.09, 95% CI 1.06-1.12, P < 0.001). There were no associations with low output. Death or clinical deterioration was associated with severe congestion (OR 1.6, 95% CI 1.2-2.2, P = 0.002), but not with CI alone. However, children with both low output and severe congestion were at highest risk (OR 1.9, 95% CI 1.1-3.5, P = 0.03). Conclusion Congestion is more common than low cardiac output in children with end-stage heart failure and correlates with NYHA/Ross classification and end-organ dysfunction. Children with both congestion and low output have the highest risk of death or clinical deterioration.

A contemporary review of paediatric heart transplantation and mechanical circulatory support

Improvements in the care of children with cardiomyopathy, CHDs, and acquired heart disease have led to an increased number of children surviving with advanced heart failure. In addition, the advent of more durable mechanical circulatory support options in children has changed the outcome for many patients who otherwise would have succumbed while waiting for heart transplantation. As a result, more children with end-stage heart failure are being referred for heart transplantation, and there is increased demand for a limited donor organ supply. A review of important publications in the recent years related to paediatric heart failure, transplantation, and mechanical circulatory support show a trend towards pushing the limits of the current therapies to address the needs of this growing population. There have been a number of publications focussing on previously published risk factors perceived as barriers to successful heart transplantation, including elevated pulmonary vascular resistance, medication non-adherence, re-transplantation, transplantation of the failed Fontan patient, and transplantation in an infant or child bridged with mechanical circulatory support. This review will highlight some of these key articles from the last 3 years and describe recent advances in the understanding, diagnosis, and management of children with end-stage heart disease.

Heart failure following the norwood procedure: An analysis of the single ventricle reconstruction trial

BACKGROUND Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure. METHODS We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure. RESULTS Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p < 0.05). CONCLUSIONS By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure.

Multiple mechanical support modalities and cardiac transplantation in a young child with corrected transposition

From the Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Division of Pediatric Critical Care, Department of Pediatrics, and Division of Pediatric Cardiology, Department of Pediatrics, Medical College of Wisconsin and Herma Heart Institute at Children’s Hospital of Wisconsin, Milwaukee, Wis; and Division of Cardiothoracic Surgery, Department of Surgery, Cincinnati Children’s Hospital and Medical Center, Cincinnati, Ohio; and the Division of Cardiothoracic Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication Oct 17, 2017; revisions received Nov 10, 2017; accepted for publication Nov 19, 2017. Address for reprints: Ronald K. Woods, MD, PhD, Herma Heart Institute and Children’s Hospital of Wisconsin, 9000 W Wisconsin Ave, Milwaukee, WI 53226 (E-mail: RWoods@chw.org). J Thorac Cardiovasc Surg 2017;-:e1-3 0022-5223/

Mechanical Dyssynchrony and Abnormal Regional Strain Promote Erroneous Measurement of Systolic Function in Pediatric Heart Transplantation

36.00 Copyright 2017 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2017.11.080 Modifications permitting placement of an intracorporeal LVAD in a 13-kg patient.

Current Topics and Controversies in Pediatric Heart Transplantation: Proceedings of the Pediatric Heart Transplantation Summit 2017

BACKGROUND Clinical experience suggests that measurement of left ventricular (LV) ejection fraction (EF) using two-dimensional echocardiography (2DE) is often at variance with results of three-dimensional echocardiography (3DE) in patients who have undergone heart transplantation (HT). The aim of this study was to test the hypothesis that LV mechanical dyssynchrony and abnormal regional strain are present in asymptomatic pediatric HT patients and that they promote errors in the measurement of LV function when 2DE is used. METHODS HT subjects and normal volunteer children were prospectively enrolled. All had normal estimated right ventricular systolic pressure and function. LV EF, global and regional strain, and systolic dyssynchrony index (SDI) were quantified using real time 3DE. SDI was determined from volume-time curves of the 16 LV segments and expressed as the standard deviation of the heart rate-corrected time to reach minimal segmental systolic volume. Septal strain was defined as the average of five segments in the interventricular septum. In addition to 3DE, the Teichholz, biplane Simpson, and bullet (5/6 area-length) methods were used to measure EF using 2DE in each subject. Ninety-three examinations were done: 40 in the 40 normal control subjects (mean age, 14.6 ± 10.6 years; 10 male) and 53 in 36 HT subjects (mean age, 10.3 ± 6.2 years; 21 male). RESULTS SDI was greater in HT patients (mean, 6.2 ± 4.3%) than in normal controls (mean, 2.2 ± 1.1%) (P < .0001). Global and septal strain was lower in HT patients than in normal controls. EF divergence (absolute difference between two- and three-dimensional EFs) was greater in HT patients (mean, 3.8 ± 2.2%) than in normal controls (mean, 0.7 ± 0.5%) (P < .0001). EF divergence had a strong positive correlation with SDI (adjusted r² = 0.46, P < .001) and negative correlations with all measures of strain (range of adjusted r² values, 0.13-0.32). SDI had no particular relation to LV mass or to QRS duration. CONCLUSIONS Children after HT have abnormal LV mechanics characterized by greater dyssynchrony and lower strain. These features correlate with, and possibly contribute to differences between measurements by 2DE and 3DE. EF should be calculated using 3DE in this population and others with dyssynchrony and regional strain abnormalities.

Heart Failure in the Neonate

In October 2017, a pediatric heart transplant summit was held in Seattle—the first of its kind internationally—which focused solely upon controversies in pediatric end-stage heart failure management and pediatric heart transplantation. We selected five of the most popular and contentious topics and asked the speakers to provide a position paper. Worldwide, the vast majority of programs perform only a handful of pediatric heart transplants a year. Because of this, these “orphan” areas of investigation provide an opportunity for us as a community to aggregate our collective knowledge, which may represent the only viable way that we might sort through these complex and controversial issues in the field. We hope this represents the first of many such conferences and that this initial selection of papers encourages us to begin this collaborative process.