Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial.

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

Entrustable Professional Activities and Their Relevance to Pediatric Cardiology Training.

Entrustable professional activities (EPAs) have become a popular framework for medical trainee assessment and a supplemental component for milestone and competency assessment. EPAs were developed to facilitate assessment of competencies and furthermore to facilitate translation into clinical practice. In this review, we explore the rationale for the introduction of EPAs, examine whether they fulfill the promise expected of them, and contemplate further developments in their application with specific reference to training in pediatric cardiology.

Advanced fellowship training for cardiology fellows in acute care cardiology.

Hospitalised children have become more medically complex and increasingly require specialised teams and units properly equipped to care for them. Within paediatric cardiology, this trend, which is well demonstrated by the expansion of cardiology-specific ICUs, has more recently led to the development of acute care cardiology units to deliver team-based and condition-focused inpatient care. These care teams are now led by paediatric cardiologists with particular investment in the acute care cardiology environment. Herein, we describe the foundation and development of an Acute Care Cardiology Advanced Training Fellowship to meet the clinical, scholarly, and leadership training needs of this emerging care environment.

Is the Use of Routine Echocardiograms Warranted in Large Pediatric Burns?

Cardiac dysfunction can develop in large pediatric burns during the acute and recovery phase. When occurring in this population, the cardiac abnormality appears as left ventricular dysfunction or dilated cardiomyopathy. Recent studies have demonstrated perioperative and long-term cardiac dysfunction resulting in longer hospital stays for patients over 40% total body surface area. The objective of this study was to assess if early use of echocardiograms in large burns would allow for early recognition of patients at risk for cardiac dysfunction. Pediatric burn patients ages 0 to 18 years who sustained a burn injury of 30% TBSA or more or developed cardiac dysfunction during hospital course were evaluated. Echocardiograms were obtained upon admission with monthly repeats until three normal studies were attained or the patient was discharged and when symptomatic. Of the 130 acute burn patients admitted during 7/2017 to 10/2018, 10 patients met criteria for enrollment in this study. The average age was 5 years (0.8-10 years), 70% were males and 90% sustained flame injuries.Total TBSA average was 45% (24-70%) with average full-thickness burns of 33% (0-67%). Twenty echocardiogram studies were obtained. One patient with 25% TBSA burn, demonstrated severe left ventricular dysfunction with an ejection fraction (EF) of 25% from post-arrest myocardial stunning. Repeat echocardiogram studies demonstrated full recovery with normal EF. The remaining patients, despite large TBSA injuries, did not exhibit any abnormalities on echocardiogram examinations. No cardiac interventions were required. Use of echocardiograms is best performed on symptomatic burn patient populations.

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

Fontan-associated protein-losing enteropathy and post‒heart transplant outcomes: A multicenter study.

BACKGROUND: The influence of Fontan-associated protein-losing enteropathy's (PLE) severity, duration, and treatment on heart transplant (HTx) outcomes is unknown. We hypothesized that long-standing PLE and PLE requiring more intensive therapy are associated with increased post-HTx mortality. METHODS: This 12-center, retrospective cohort study of post-Fontan patients with PLE referred for HTx from 2003 to 2015 involved collection of demographic, medical, surgical, and catheterization data, as well as PLE-specific data, including duration of disease, intensity/details of treatment, hospitalizations, and complications. Factors associated with waitlist and post-HTx outcomes and PLE resolution were sought. RESULTS: Eighty patients (median of 5 per center) were referred for HTx evaluation. Of 68 patients listed for HTx, 8 were removed due to deterioration, 4 died waiting, and 4 remain listed. In 52 patients undergoing HTx, post-HTx 1-month survival was 92% and 1-year survival was 83%. PLE-specific factors, including duration of PLE pre-HTx, pre-HTx hospitalizations, need for/frequency of albumin replacement, PLE therapies, and growth parameters had no association with post-HTx mortality. Immunosuppressant regimen was associated with mortality; standard mycophenolate mofetil immunotherapy was used in 95% of survivors compared with only 44% of non-survivors (p = 0.03). Rejection (53%) and infection (42%) post-HTx were common, but not associated with PLE-specific factors. PLE resolved completely in all but 1 HTx survivor at a median of 1 month (interquartile range 1 to 3 months); resolution was not affected by PLE-specific factors. CONCLUSIONS: PLE severity, duration, and treatment do not influence post-HTx outcome, but immunosuppressive regimen may have an impact on survival. PLE resolves in nearly all survivors.

Pediatric Heart Transplantation Long-Term Survival in Different Age and Diagnostic Groups: Analysis of a National Database.

BACKGROUND: The purpose of this study was to evaluate differences in long-term survival without the influence of early mortality, and to identify factors associated with one-year conditional ten-year survival after heart transplantation (HTx) across different age and diagnostic groups. METHODS: Organ Procurement and Transplant Network data from January 1990 to December 2005 were used. Cohort was divided according to age (infants [<1 year], children [>1-10 years], and adolescents [11-18 years]) and diagnosis (cardiomyopathy and congenital heart disease [CHD]). Factors associated with one-year conditional ten-year survival were identified using multivariable logistic regression and using a case-control design. RESULTS: One-year conditional ten-year survivors included 1,790 patients compared to 1,114 patients who died after the first posttransplant year and within ten years of transplant with a median follow-up of 4.8 years. Predictors of one-year conditional ten-year survival for infants were recipient's Caucasian race (odds ratio [OR]: 1.9, 95% confidence interval [CI]: 1.3-2.7) and donor-recipient weight ratio (OR: 0.8, 95% CI: 0.6-1); for children: Caucasian race (OR: 1.6, 95% CI: 1.2-2.1), retransplantation (OR: 0.4, 95% CI: 0.2-0.6), and transplantation after the year 2000 (OR: 1.5, 95% CI: 1.1-2.1); for adolescents only Caucasian race (OR: 2.5, 95% CI: 1.9-2.3). In both CHD and cardiomyopathy, adolescents had worse survival compared to infants and children. There was an era effect with improved survival after 2000. Male gender was a predictor of survival in cardiomyopathy group. CONCLUSION: Predictors of one-year conditional ten-year survival varied among groups. These data and analyses provide important information that may be useful to clinicians, particularly when counseling patients and families regarding expectations of survival after pediatric HTx.

Arrhythmic Burden and Ambulatory Monitoring of Pediatric Patients with Cardiomyopathy.

BACKGROUND: Pediatric patients with cardiomyopathy (CM) are at risk for sudden cardiac death (SCD), likely driven by arrhythmic etiologies. OBJECTIVES: Describe arrhythmia burden and Holter utility in pediatric CM including: hypertrophic CM (HCM), dilated CM (DCM), and restrictive CM (RCM). METHODS: Retrospective cohort study of patients <21 years with CM. Patient demographics, arrhythmic history, and genetic status were reviewed including outcomes of death, aborted SCD, and device shocks. Holter findings were analyzed over the prior 5 years including clinically significant findings and resulting changes to management. Analysis for the composite outcomes of death, aborted SCD, and appropriate shock were performed using logistic regression with backward elimination. RESULTS: One hundred and forty-six patients were included: 83 HCM, 54 DCM, and nine RCM (mean 13 ± 6 years). A total of 23% of patients had defibrillators. There were six deaths (two SCD), four patients with appropriate device therapies, and four aborted SCD episodes. In total, 305 Holter monitors were reviewed. Six Holters had significant findings, all nonsustained ventricular tachycardia. Two Holters resulted in changes in management, both defibrillator implantations. Twelve patients had one or more of the conditions defining the composite outcome. Using logistic regression, clinical history of ventricular arrhythmia, frequent premature ventricular complexes, and CM type were included as potential independent predictors in the final model and clinical ventricular arrhythmia and RCM disease were associated with the composite outcome. CONCLUSIONS: SCD and device therapies were relatively rare. Routine Holter screening rarely demonstrated significant findings or changed clinical care. Clinical history of ventricular arrhythmia was associated with poor clinical outcome.

Health-related quality of life in children with heart failure as perceived by children and parents.

Advancements in paediatric heart failure management have resulted in improved survival and a focus on long-term outcomes including health-related quality of life. We compared health-related quality of life in children with heart failure with healthy patients, children with chronic conditions, and children with cardiovascular disease. Families (n=63) and children (n=73) aged 2-20 years with heart failure were enrolled and compared with data previously published for healthy patients (n=5480), those with chronic conditions (n=247), and those with cardiovascular disease (n=347). Patients and parents completed the PedsQL 4.0 and the Cardiac 3.0 Module health-related quality-of-life questionnaires. PedsQL scores including Total, Psychosocial Health Summary, and Physical were compared between groups. In general, patients with heart failure had lower scores than the healthy population (p=0.001), and comparable scores with those with chronic conditions. Parents perceived no difference in physical scores for children with heart failure when compared with healthy children, and perceived higher scores for children with heart failure when compared with those with chronic conditions (p⩽0.003). Furthermore, children with heart failure had decremental health-related quality-of-life scores as the American Heart Association stage of heart failure increased, such that patients with stage C heart failure had scores similar to children with severe cardiovascular disease. Children with heart failure reported significantly impaired health-related quality of life compared with healthy children and similar scores compared with children with chronic conditions. Parental perceptions appear to underestimate these impairments. Children with heart failure appear to have progressive impairment of health-related quality of life with advancing stage of heart failure.

Preventing pediatric cardiomyopathy: a 2015 outlook.

Cardiomyopathies in children encompass a broad range of diseases, both genetic and acquired, which manifest as a primary cardiac disorder or as a cardiomyopathy secondary to systemic disease. The burden of this group of disorders is substantial, and growing on a global scale. The availability of disease altering treatments is limited, and therefore a focused review on the prevention of cardiomyopathies is justified. In this review, we address the prevention of cardiomyopathy in children by dealing with the root causes of disease at a molecular, clinical and population level. Recent years have yielded promising returns in basic research related to gene-targeted therapy, specific anti-viral therapies and modification of the effects of cardiotoxic drugs. Much work remains to be done in the fields of vaccine development, public health and adoption of available treatments. Effective research in this field will require that diagnostic methods are both refined, and made available more broadly, from imaging to gene testing. Much of our knowledge today is derived from the use of registries, which have successfully catalogued the detailed phenotype of affected patients, and provided long-term longitudinal follow up of affected individuals.

Managing heart failure in adults with congenital heart disease.

OPINION STATEMENT: The current era of cardiology has seen a significant increase in the number of adults living with congenital heart disease (CHD). Although advances in medical and surgical management have resulted in approximately 90 % of children with CHD living into adulthood, many suffer from late complications, with myocardial dysfunction as the leading cause of morbidity and mortality. The heterogeneity of the adult congenital heart disease (ACHD) population has presented a challenge, as there are only limited data regarding appropriate treatment modalities. Given the growing ACHD population and the high morbidity and mortality related to myocardial dysfunction, a comprehensive approach to heart failure (HF) care is recommended in conjunction with ACHD and HF specialty care. The field must focus on developing research strategies to leverage existing and future medical and surgical treatment options in order to improve outcomes in this diverse population.

Outcomes, arrhythmic burden and ambulatory monitoring of pediatric patients with left ventricular non-compaction and preserved left ventricular function.

Pediatric patients with left ventricular noncompaction (LVNC) and severe ventricular dysfunction are at risk for sudden death. The aims of this study were to (1) evaluate outcomes, (2) describe arrhythmic burden on Holter monitoring, and (3) analyze the utility of Holter monitoring and its impact on care in pediatric patients with LVNC and preserved or mild ventricular dysfunction. This was a retrospective study including patients <21 years of age with LVNC and ejection fractions ≥45%. Demographic and outcome data were analyzed. Individual and cumulative Holter data were evaluated for all patients. Arrhythmias, conduction system disease, and symptoms were analyzed for each Holter recording. The incidence of significant findings and the impact on care were determined for each study. Outcome and Holter data were compared between patients on the basis of the ejection fraction (≥55% [normal] or ≥45% to <55% [mild]). This study included 72 patients, 65 with normal function and 7 with mild dysfunction (mean age 13 years). There was a single death in the cohort, which was sudden in nature. Simple ventricular ectopy was common on Holter monitoring and more common in patients with mild dysfunction (86% vs 27%, p = 0.005). Significant Holter findings (4% vs 6%) and changes to patient care (2% vs 4%) improved with cumulative Holter monitoring. In conclusion, in contrast to patients with severe dysfunction, pediatric patients with LVNC and normal or mild dysfunction have significantly better outcomes. However, worsening LV systolic function was correlated with increasing ventricular ectopy. The role of Holter monitoring is unknown, but it may have utility in patient care if used as part of ongoing screening.

Correlation of precordial voltages to left ventricular mass on echocardiogram in adolescent patients with hypertrophic cardiomyopathy compared with that in adolescent athletes.

Electrocardiograms continue to be part of screening programs for athletes and familial hypertrophic cardiomyopathy (HC). Whether electrocardiographic (ECG) findings of left ventricular (LV) hypertrophy can distinguish between healthy populations and those with HC remains unclear. We sought to (1) analyze the relation between ECG voltage and LV mass in patients with HC and (2) evaluate ECG characteristics of patients with phenotypical HC. Retrospective cohort of patients with HC aged 13 to 18 years. Relation between ECG voltages (RV6, SV1, and RV6 + SV1) and echocardiogram measurements of LV mass was investigated using smoothing splines to display relations and compared with those in a prospectively obtained population of adolescents. Frequency of abnormal LV voltages and nonvoltage ECG changes (Q waves, T-wave changes, and ST changes) were analyzed for association with HC. Fifty-three patients with HC (72% men) were age and gender matched to 104 control patients. Smoothing splines demonstrated that parabolic rather than linear relations existed between LV mass and SV1, RV6, and RV6 + SV1 in patients with HC and not the control cohort. LV hypertrophy by ECG voltage criteria was present in 34% of patients with HC and associated with poor sensitivity (29%). In patients with HC, 56% demonstrated nonvoltage ECG abnormalities and were associated with improved sensitivity (68%) and high specificity (94%). In conclusion, there is a parabolic relation between LV voltages and LV mass in adolescents with HC that may lead to "pseudonormalization." Voltage abnormalities were associated with poor sensitivity, whereas nonvoltage criteria were associated with improved sensitivity with high specificity.

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease.

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti-coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti-coagulation regimen to coincide with changes in the inflammatory state.

Pediatric heart transplant waiting list mortality in the era of ventricular assist devices.

BACKGROUND: Earlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs. METHODS: United Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged ≤ 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2). RESULTS: Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p < 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p < 0.001) and was associated with better waiting list survival (p < 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p < 0.001). Independent predictors of waiting list mortality included weight < 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1-6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9-3.0), blood type O (OR, 2.2; 95% CI, 1.8-2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1-2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4-2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2-2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4-7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4-4.6), blood type A (OR, 2.2; 95% CI, 1.8-2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2-3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4-2.2), and white race (OR 1.3; 95% CI, 1.1-1.6). CONCLUSIONS: Despite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant.

Health-related quality of life assessment in children followed in a cardiomyopathy clinic.

As our ability to diagnosis cardiomyopathy matures and genetic testing becomes more widespread, there has been an increase in the number of children followed for cardiomyopathy. The purpose of this study was to compare health-related quality of life (HRQoL) between children with cardiomyopathy and healthy controls and with children seen in clinic who are at risk for the development of cardiomyopathy. Patient and parent-proxy perspectives were obtained using the Pediatric Quality of Life Inventory (PedsQL(TM)) 4.0 Core Scales (ages 2-18 years) and the disease-specific Cardiac Module. Cardiomyopathy physicians' perceptions of the impact of cardiomyopathy on the functional status of the patients were collected. In addition, data regarding disease-specific medical and socioeconomic information were collected from chart review and parental report. The questionnaires were completed by 100 parent-proxies and 71 children. The PedsQL(TM) scores reported by children and their parent-proxies were compared to scores reported by pediatric norms. Compared to healthy controls, patients followed in a pediatric cardiomyopathy clinic scored lower in Total score when compared to pediatric norms (80.7 vs 86.4, p = 0.002). Interestingly, children with a family history of cardiomyopathy who are at risk for developing the disease scored similar to those children with a diagnosis of cardiomyopathy. Parental and patients perceptions were discrepant when compared, which may deter appropriate referral to behavioral health services. These results should encourage cardiomyopathy clinics to screen all patients for HRQoL impairments and to have behavioral services available to assist these children.

Pediatric mechanical circulatory support.

Mechanical circulatory support (MCS) in the pediatric heart failure population has a limited history especially for infants, and neonates. It has been increasingly recognized that there is a rapidly expanding population of children diagnosed and living with heart failure. This expanding population has resulted in increasing numbers of children with medically resistant end-stage heart failure. The traditional therapy for these children has been heart transplantation. However, children with heart failure unlike adults do not have symptoms until they present with end-stage heart failure and therefore, cannot safely wait for transplantation. Many of these children were bridged to heart transplantation utilizing extracorporeal membranous oxygenation as a bridge to transplant which has yielded poor results. As such, industry, clinicians, and the government have refocused interest in developing increasing numbers of MCS options for children living with heart failure as a bridge to transplantation and as a chronic therapy. In this review, we discuss MCS options for short and long-term support that are currently available for infants and children with end-stage heart failure.

Cardiac catheterisation of patients with common arterial trunk and transposition of the great arteries.

Cardiac catheterisation continues to play an important role in the long-term management of patients with common arterial trunk and transposition of the great arteries. Although non-invasive imaging has largely eliminated the need for diagnostic catheterisation in newborns with these congenital cardiac lesions, cardiac catheterisation is an important tool for the diagnosis of a variety of problems encountered after surgical intervention, and allows interventions to be performed when feasible. We review the indications for cardiac catheterisation and describe the specifics for various interventional procedures for these patients in this manuscript.