Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association.

This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Rejection surveillance in pediatric heart transplant recipients: Critical reflection on the role of frequent and long-term routine surveillance endomyocardial biopsies and comprehensive review of non-invasive rejection screening tools.

BACKGROUND: Despite significant medical advances in the field of pediatric heart transplantation (HT), acute rejection remains an important cause of morbidity and mortality. Endomyocardial biopsy (EMB) remains the gold-standard method for diagnosing rejection but is an invasive, expensive, and stressful process. Given the potential adverse consequences of rejection, routine post-transplant rejection surveillance protocols incorporating EMB are widely employed to detect asymptomatic rejection. Each center employs their own specific routine rejection surveillance protocol, with no consensus on the optimal approach and with high inter-center variability. The utility of high-frequency and long-term routine surveillance biopsies (RSB) in pediatric HT has been called into question. METHODS: Sources for this comprehensive review were primarily identified through searches in biomedical databases including MEDLINE and Embase. RESULTS: The available literature suggests that the diagnostic yield of RSB is low beyond the first year post-HT and that a reduction in RSB intensity from high-frequency to low-frequency can be done safely with no impact on early and mid-term survival. Though there are emerging non-invasive methods of detecting asymptomatic rejection, the evidence is not yet strong enough for any test to replace EMB. CONCLUSION: Overall, pediatric HT centers in North America should likely be doing fewer RSB than are currently performed. Risk factors for rejection should be considered when designing the optimal rejection surveillance strategy. Noninvasive testing including emerging biomarkers may have a complementary role to aid in safely reducing the need for RSB.

Heart transplantation in an infant with Williams-Beuren syndrome and rapidly progressive ischemic cardiomyopathy.

Ischemic cardiomyopathy with resultant refractory HF may occur in patients with WBS, often as the result of coronary involvement with SVAS. The rapid development of arteriopathy at a young age raises concerns regarding transplant candidacy due to progressive stenoses at other arterial sites with potential detrimental impact on long-term heart graft function. We report a 2-month-old male infant diagnosed with mild aortic stenosis during the neonatal period, but subsequently developed rapidly progressive supravalvar and coronary artery stenoses leading to cardiogenic shock due to myocardial ischemia. The presentation led to the diagnosis of WBS. He required prolonged CPR including ECMO therapy. He subsequently underwent LVAD implantation as bridge to transplant and 4 days later heart transplantation. His post-operative course was complicated by prolonged mechanical ventilation and extended intensive care unit and hospital stays. However, at follow-up 18 months post-transplant he continues to have normal graft function with mild, non-progressive residual coarctation of aorta and non-progressive moderately hypoplastic pulmonary arteries.

A comprehensive strategy in donor acceptance: Impact on pediatric waitlist and heart transplant outcomes.

Significant inter- and intra-center practice variability is present in pediatric donor heart acceptability. This may contribute to variation in the donor refusal rate and may impact waitlist time, morbidity, mortality, and transplant rates. In order to reduce practice variability, our center developed and implemented a comprehensive strategy regarding donor acceptance in September 2017. The aim of this study was to assess the impact of this strategy on waitlist time and outcomes as well as early post-transplant outcomes. We performed a single-center, retrospective analysis of all pediatric (<18 years) patients listed for single-organ heart transplant at our center from September 2015 to September 2018. Patients were divided into those listed before (Group 1) and after implementation of the comprehensive strategy (Group 2). The primary end-point was waitlist time. Secondary end-points included waitlist removal due to death or clinical deterioration, donor refusals per listed patient, early post-transplant outcomes (graft failure, mechanical ventilation time, inotropic support, length of hospital stay) and 1-year post-transplant survival. Of 78 listed patients, 54 were transplanted (29 in Group 1), 9 were removed due to death or clinical deterioration (7 in Group 1) and 15 were removed due to clinical improvement (12 in Group 1). The waitlist time was significantly shorter in Group 2 (17 days, IQR 7-53) vs Group 1 (90 days, IQR 14-162); P = .006. The number of donor refusals was lower in Group 2 (1, IQR 0-2.2) vs Group 1 (4, IQR 2-19); P < .001. The percentage of refused donors with normal function (Left ventricular ejection fraction > 50%) was lower in Group 2 vs Group 1 (53% vs 84%; P < .001). Difference in removal from the waitlist for death or deterioration in Group 2 vs Group 1 (n = 2, 7% vs n = 7, 20%, P = .18) did not reach statistical significance. There was no difference in post-transplant outcomes between groups. The waitlist time and donor refusals significantly decreased after implementation of a comprehensive donor acceptance strategy without impacting transplant outcomes. This analysis supports the need for a comprehensive approach to donor organ acceptance within a pediatric transplant center.

Utilization of Neurally Adjusted Ventilatory Assist (NAVA) Mode in Infants and Children Undergoing Congenital Heart Surgery: A Retrospective Review.

We assessed the feasibility and the impact of NAVA compared to conventional modes of mechanical ventilation in ventilatory and gas exchange parameters in post-operative children with congenital heart disease. Infants and children (age < 18 years) that underwent congenital heart surgery were enrolled. Patients were ventilated with conventional synchronized intermittent mechanical ventilation (SIMV) and subsequently transitioned to NAVA during their cardiovascular intensive care unit (CVICU) stay. The ventilatory and gas exchange parameters for the 24 h pre- and post-transition to NAVA were compared. Additional parameters assessed included pain scores and sedation requirements. Eighty-one patients met inclusion criteria with a median age of 21 days (interquartile range 13 days-2 months). The majority of patients enrolled (75.3%) had complex congenital heart disease with high surgical severity scores. The transition to NAVA was tolerated by all patients without complications. The mean peak inspiratory pressure (PIP) was 1.8 cm H2O lower (p < 0.001) and mean airway pressure (Paw) was 0.5 cm H2O lower (p = 0.009) on NAVA compared to conventional modes of mechanical ventilation. There was no significant difference in patients' respiratory rate, tidal volume, arterial pH, pCO2, and lactate levels between the two modes of ventilation. There was a decreased sedation requirement during the time of NAVA ventilation. Comfort scores did not differ significantly with ventilator mode change. We concluded that NAVA is safe and well-tolerated mode of mechanical ventilation for our cohort of patients after congenital heart surgery. Compared to conventional ventilation there was a statistically significant decrease in PIP and Paw on NAVA.

Uncertain benefit of statins in pediatric heart transplant recipients: A PHTS analysis.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure in pediatric heart transplant recipients (HTRs). Early statin use has been shown to reduce CAV incidence and all-cause mortality in adult HTRs. We sought to evaluate the contemporary prevalence and trends of statin use in pediatric HTRs and the association between statin use with CAV development and graft failure. METHODS: Patients aged <17 years at the time of primary heart transplant who survived to ≥3 years without CAV were identified from the Pediatric Heart Transplant Society database (2001-2018). Statin use in the first 3 years posttransplant was defined as consecutive, intermediate, or absent. Kaplan-Meier survival, multivariable modeling, and propensity score-matched analyses evaluated associations between statin use and CAV incidence and graft survival, with subanalyses performed on subjects aged ≥10 years at transplant. RESULTS: Among 3,485 (of which 1,086 aged ≥10 years) HTRs, 584 (17%) received consecutive statin therapy, 647 (19%) received intermediate use, and 2,254 (65%) received no statin therapy. Statin use varied widely between sites, with increasing use in the ≥10-year-old cohort over time. By multivariate analysis, statin use was not associated with graft loss. Consecutive statin use was also not associated with graft survival or freedom from CAV development when compared to absent statin use in unmatched or propensity-matched analyses. CONCLUSIONS: While statins remain commonly utilized in pediatric HTRs, early consecutive statin therapy did not decrease CAV incidence or graft loss. The differing effects of statins on CAV development and progression in pediatric vs adult HTRs suggest differing risk and mediating factors and require further study.

Center Donor Refusal Rate Is Associated With Worse Outcomes After Listing in Pediatric Heart Transplantation.

BACKGROUND: Pediatric donor heart acceptability differs among transplant centers. However, the impact of center donor acceptance on waitlist and posttransplant outcomes has not been investigated. The aim of our study was to investigate associations between transplant center refusal rate (RR) and outcomes after listing. METHODS: Retrospective analysis was performed using United Network for Organ Sharing/Organ Procurement and Transplant Network pediatric (<18 y) heart transplant data from 2007 to 2017. Center RR was defined as the median number of refusals per listed patient. Associations between RR center quartile and waitlist time, waitlist removal for death or clinical deterioration, posttransplant survival, and survival after listing were investigated. RESULTS: There were 5552 listed patients in 59 centers who met inclusion criteria. The lowest quartile RR centers had a median RR of ≤1 per listed patient, and highest RR centers percentile had a median RR of ≥4. Highest RR centers had shorter time to first offer (19 versus 38 d; P < 0.001), with longer waitlist times (203 versus 145 d; P < 0.001), were more likely to remove patients from the waitlist due to death or deterioration (24.1% versus 14.6%; P < 0.001), less likely to transplant listed patients (63.1% versus 77.6%; P < 0.001), and had a lower likelihood of survival 1 year after listing (79.2% versus 91.6%; odds ratio, 1.6; 95% confidence interval, 1.2-2.0; P < 0.001) compared with low RR centers. CONCLUSIONS: Patients listed at high RR centers had worse survival from listing despite having shorter times to first offer.

Utilization and outcomes in biventricular assist device support in pediatrics.

OBJECTIVE: Patients with biventricular assist devices (BiVADs) have worse outcomes than those with left ventricular assist devices (LVADs). It is unclear whether these outcomes are due to device selection or patient factors. We used propensity score matching to reduce patient heterogeneity and compare outcomes in pediatric patients supported with BiVADs with a similar LVAD cohort. METHODS: The Pedimacs registry was queried for patients who were supported with BiVAD or LVAD. Patients were analyzed by BiVAD or LVAD at primary implant and the 2 groups were compared before and after using propensity score matching. RESULTS: Of 363 patients who met inclusion criteria, 63 (17%) underwent primary BiVAD support. After propensity score matching, differences between cohorts were reduced. Six months after implant, in the BiVAD cohort (LVAD cohort) 52.5% (42.5%) had been transplanted; 32.5% (40%) were alive with device, and 15% (10%) had died. Survival was similar between cohorts (P = .31, log-rank), but patients with BiVADs were more likely to experience a major adverse event in the form of bleeding (P = .04, log-rank). At 1 week and 1 and 3 months' postimplant, the percentage of patients on mechanical ventilation, on dialysis, or with elevated bilirubin was similar between the 2 groups. CONCLUSIONS: When propensity scores were used to reduce differences in patient characteristics, there were no differences in survival but more major adverse events in the patients with BiVADs, particularly bleeding. Differences in unmatched patient outcomes between LVAD and BiVAD cohorts likely represent differences in severity of illness rather than mode of support.