Diagnosis and Management of Cancer Treatment-Related Cardiac Dysfunction and Heart Failure in Children.

It is disheartening for parents to discover that their children have long-term cardiac dysfunction after being cured of life-threatening childhood cancers. As the number of childhood cancer survivors increases, early and late oncology-therapy-related cardiovascular complications continues to rise. It is essential to understand that cardiotoxicity in childhood cancer survivors is persistent and progressive. A child's cancer experience extends throughout his lifetime, and ongoing care for long-term survivors is recognized as an essential part of the cancer care continuum. Initially, there was a lack of recognition of late cardiotoxicities related to cancer therapy. About 38 years ago, in 1984, pioneers like Dr. Lipshultz and others published anecdotal case reports of late cardiotoxicities in children and adolescents exposed to chemotherapy, including some who ended up with heart transplantation. At that time, cardiac tests for cancer survivors were denied by insurance companies because they did not meet appropriate use criteria. Since then, cardio-oncology has been an emerging field of cardiology that focuses on the early detection of cancer therapy-related cardiac dysfunction occurring during and after oncological treatment. The passionate pursuit of many healthcare professionals to make life better for childhood cancer survivors led to more than 10,000 peer-reviewed publications in the last 40 years. We synthesized the existing evidence-based practice and described our experiences in this review to share our current method of surveillance and management of cardiac dysfunction related to cancer therapy. This review aims to discuss the pathological basis of cancer therapy-related cardiac dysfunction and heart failure, how to stratify patients prone to cardiotoxicity by identifying modifiable risk factors, early detection of cardiac dysfunction, and prevention and management of heart failure during and after cancer therapy in children. We emphasize serial longitudinal follow-ups of childhood cancer survivors and targeted intervention for high-risk patients. We describe our experience with the new paradigm of cardio-oncology care, and collaboration between cardiologist and oncologist is needed to maximize cancer survival while minimizing late cardiotoxicity.

Impact of induction therapy on cytomegalovirus infection and post-transplant outcomes in pediatric heart transplant recipients receiving routine antiviral prophylaxis.

OBJECTIVES: Induction therapy has been increasingly used in pediatric heart transplantation. This study evaluated the impact of anti-thymocyte globulin (ATG) versus basiliximab as induction therapy on post-transplant cytomegalovirus (CMV) infection, rejection at 1 year, coronary allograft vasculopathy (CAV), and mortality in pediatric heart transplant recipients receiving antiviral prophylaxis. RESULTS: Of the 96 patients (age < 18 years) analyzed, 46 (47.9%) patients received basiliximab, and 50 (52.1%) received ATG. Median follow-up was 3.0 (IQR, 1.7-4.9) years with 32.3% reporting CMV infection. The ATG group, as compared with the basiliximab group, had similar incidences of CMV infection (36% vs. 28.3%, p = .418), CMV viremia (22% vs. 19.6%, p = .769), and CMV-positive tissue biopsy (30% vs. 22%, p = .486). The ATG group had lower incidences of rejection at 1 year (16% vs. 36.9%, p = .022) and CAV (4% vs. 23.9%, p = .006) with no difference in mortality (8% vs. 15.2%, p = .343), compared with the basiliximab group. Multivariate analysis showed that induction with ATG was associated with a lower risk of rejection at 1 year (OR, .31; 95% CI, .09-.94; p = .039) with no impact on the incidences of CMV infection (HR, 2.06; 95% CI, .54-7.89; p = .292), CAV (HR, .30; 95% CI, .04-2.58; p = .275), and mortality (HR, .39; 95% CI, .09-1.82; p = .233) compared to basiliximab induction. DISCUSSION AND CONCLUSIONS: In conclusion, induction with ATG was associated with reduction in risk of rejection at 1 year with no effects on CMV infection, CAV, and mortality in pediatric heart transplant recipients with universal antiviral prophylaxis compared with basiliximab induction therapy.

Detection of parvovirus B19 and human herpesvirus 6 in pediatric dilated cardiomyopathy: Impact after heart transplantation.

OBJECTIVES: The aim of this study is to evaluate HHV-6 and PVB19 infection using polymerase chain reaction (PCR) and immunofluorescent assay (IFA) in the myocardium of pediatric patients with dilated cardiomyopathy (DCM) and the impact of viral persistence in the cardiac allograft after heart transplantation (HT). METHODS: Multiplex droplet digital PCR was used to analyze the prevalence of viral sequences in myocardial samples from 48 pediatric DCM patients and 10 control subjects. Of the 48 DCM patients, 44 underwent HT. After HT, consecutive endomyocardial biopsy (EMB) samples were analyzed for the presence of PVB19 and HHV-6 antigens using IFA and the patients were evaluated for rejections, coronary vasculopathy, and graft loss. RESULTS: Of the 48 DCM patients, 14 had positive viral PCR results in explanted/autopsy hearts. Among them, PVB19 was found in 8/48, HHV6 in 4/48, both PVB19 and HHV6 in 1/48, and enterovirus in one, but no adenovirus was found. The EMB samples obtained after HT were positive for PVB19 and HHV-6 in 7/44 and 3/44 cases, respectively. Viral presence in both the explanted heart and the cardiac allograft was demonstrated in 4 patients, 3 of whom were positive for PVB19, and one of whom was positive for HHV-6 pretransplant. Coronary vasculopathy and graft loss were more common in patients with PVB19-positive myocardial tissues versus those who were PVB19-negative. CONCLUSIONS: There is an association between PVB19 and HHV-6 infection and DCM in children. The study suggests the persistence of PVB19 and HHV-6 in the host can lead to subsequent viral reactivation in the transplanted heart, even in those recipients who do not have active myocarditis. PVB19 in the cardiac allograft tended toward higher adverse post-HT events.

Correlation of gene expression profiling score, cardiac hemodynamics and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant recipients.

OBJECTIVES: To correlate gene expression profiling scores obtained by AlloMap® with cardiac hemodynamics, cardiac allograft vasculopathy (CAV), and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant (HT) recipients. METHODS: Single-institution retrospective study of 210 AlloMap scores obtained concomitantly with cardiac catheterization and echocardiogram from 55 children during follow-up after cardiac transplantation. RESULTS: The median age at HT was 5.1 years (range, 0.9-14.1), with 29 males and 26 females. AlloMap scores were high in <2 years vs ≥2 years of age at the time of HT (P = .001), and trending higher with time after HT (R2  = .04, P = .004). There was no significant difference in scores between ACR grades 0 and 1R or CAV. There was mild to modest correlation of AlloMap scores with the mean right atrial pressure (P = .002), and pulmonary capillary wedge pressure (P = .02), but no correlation was found with LV SF% (P = .3), LV EF% (P = .5), or RV FAC % (P = .8). CONCLUSIONS: Our study provides preliminary data that the AlloMap score must be studied carefully before it can be used in children, particularly in those under 2 years of age. Monitoring of serial scores for each patient could potentially reflect changes in allograft performance that may determine indications for catheterization and biopsy which needs to be validated in future studies.

Pulmonary Vascular Underperfusion Score in Premature Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension.

Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD). The underlying pathophysiology of BPD-associated PH is complex and poorly understood. Echocardiogram may underestimate the severity of pulmonary hypertensive vascular disease in severe BPD. Digital subtraction pulmonary angiography (DSPA) is a potentially useful imaging modality for evaluating changes in the pulmonary vasculature of BPD-associated PH. In this study, we objectively quantified the pulmonary hypertensive vascular changes demonstrated by DSPA using a novel pulmonary vascular underperfusion score (PVUS) and correlated the scoring system with echocardiography parameters and cardiac hemodynamics by right heart catheterization.

Reports of 2 Rare Associations of Hypoplastic Left Heart Syndrome.

This report describes 2 contrasting yet rare associations of hypoplastic left heart syndrome, 1 in a patient with pulmonary valve stenosis that was successfully surgically palliated and the other in a patient with an intact atrial septum and stenotic bilateral levoatriocardinal veins who was offered comfort care. These cases underscore the point that although both infants were born with hypoplastic left heart syndrome, the outcomes can dramatically differ as a result of anatomic and physiological variables. (Level of Difficulty: Advanced.).

Successful treatment of giant condyloma in a pediatric heart transplant recipient with topical cidofovir.

We report a case of giant condyloma that developed in a pediatric heart transplant recipient. This infection progressed for several months despite reduction in immunosuppression, topical treatment, and oral cimetidine therapy. Complete resolution was observed following 7 months of topical cidofovir, without evidence of systemic toxicity or rejection.

Sacubitril/Valsartan: potential treatment for paediatric heart failure.

The Prospective comparison of angiotensin receptor antagonist Valsartan and neprilysin inhibitor Sacubitril with angiotensin-converting enzyme inhibitor (enalapril) to determine impact on Global Mortality and Morbidity in Heart Failure trial has demonstrated that Sacubitril/Valsartan is superior to Enalapril in reducing the risks of both sudden cardiac death and death from worsening heart failure. This novel combination, Sacubitril/Valsartan, is also shown to reduce the risk of hospitalisation and progression of heart failure in adults. However, the benefit of Sacubitril/Valsartan in paediatric heart failure patients is unknown. In this review, we discuss the similarities and differences in pathophysiology of heart failure in children versus adults, and the potential role of Sacubitril/Valsartan in paediatric heart failure patients.

Cimetidine: A Safe Treatment Option for Cutaneous Warts in Pediatric Heart Transplant Recipients.

Abstract:Background andObjectives: Immunosuppressed individuals are at particularly increased risk for human papilloma virus-related infections. The primary objective of our study is to determine if there are any adverse effects associated with high-dose cimetidine treatment. A secondary objective is to report our experience with cimetidine in the treatment of cutaneous warts in pediatric heart transplant recipients. Methods and Results: This was a retrospective observational study. A total of 8 pediatric heart transplant recipients diagnosed with multiple recalcitrant warts were the subject of the study. All patients were treated with cimetidine (30-40 mg/kg/day) in two divided doses for 3 to 6 month durations. All patients had complete resolution of their lesions except 1 patient who had no clinical improvement. Of these 8 patients, one had recurrence of warts at one year follow-up, which resolved with restarting cimetidine therapy. One patient who had only 3 months of cimetidine therapy had immediate relapse after cimetidine was stopped. None of them had significant change in their tacrolimus trough, serum creatinine, and alanine transaminase levels. No adverse events were reported except one patient experienced mild gynecomastia. Conclusion: Cimetidine can be a safe and alternative treatment option for multiple warts in pediatric heart transplant recipients.

Human herpesvirus 6-induced inflammatory cardiomyopathy in immunocompetent children.

Over the last decade, human herpesvirus 6 (HHV-6) has been implicated in the etiology of pediatric myocarditis and subsequent dilated cardiomyopathy (DCM). This review provides an overview of recent literature investigating the pathophysiological relevance of HHV-6 in inflammatory cardiomyopathy. We examined 11 cases of previously published pediatric myocarditis and/or DCM associated with HHV-6 and also our experience of detection of virus particles in vascular endothelium of HHV-6 positive endomyocardial biopsy tissue by electron microscopy. The exact role of the presence of HHV-6 and its load remains controversial as the virus is also found in the heart of healthy controls. Therefore, the question remains open whether and how cardiac HHV-6 may be of pathogenetic importance. Quantitative polymerase chain reaction or mRNA testing allows differentiation between low-level latent virus found in asymptomatic myocardium and active HHV-6 infection. Although only a small number of pediatric cases have been reported in literature, HHV-6 should be considered as a causative agent of inflammatory cardiomyopathy, especially in children under three who might be experiencing a primary infection. Future studies are needed to establish a threshold for determining active infection in biopsy samples and the role of coinfections other cardiotropic viruses.

Simultaneous cross polarization to (13)C and (15)N with (1)H detection at 60kHz MAS solid-state NMR.

We describe high resolution MAS solid-state NMR experiments that utilize (1)H detection with 60kHz magic angle spinning; simultaneous cross-polarization from (1)H to (15)N and (13)C nuclei; bidirectional cross-polarization between (13)C and (15)N nuclei; detection of both amide nitrogen and aliphatic carbon (1)H; and measurement of both (13)C and (15)N chemical shifts through multi-dimensional correlation experiments. Three-dimensional experiments correlate amide (1)H and alpha (1)H selectively with (13)C or (15)N nuclei in a polypeptide chain. Two separate three-dimensional spectra correlating (1)Hα/(13)Cα/(1)H(N) and (1)H(N)/(15)N/(1)Hα are recorded simultaneously in a single experiment, demonstrating that a twofold savings in experimental time is potentially achievable. Spectral editing using bidirectional coherence transfer pathways enables simultaneous magnetization transfers between (15)N, (13)Cα(()(i)()) and (13)C'(()(i)(-1)), facilitating intra- and inter-residue correlations for sequential resonance assignment. Non-uniform sampling is integrated into the experiments, further reducing the length of experimental time.

Perioperative Care of Children with Eisenmenger Syndrome Undergoing Non-cardiac Surgery.

The Eisenmenger syndrome (ES) is a severe form of pulmonary arterial hypertension and arises in congenital heart disease with a systemic-to-pulmonary shunt. Patients with ES have multisystem involvement as a result of chronic hypoxemia with hematologic, skeletal, renal, and neurologic systems, causing significant morbidity and mortality. In contrast to pulmonary arterial hypertension, survival prospects are far superior in patients with ES and a growing number of ES patients are surviving into adulthood. As a result, many face the prospect of incidental surgery. To date, there is no guideline for the perioperative care of ES patients in children and limited data available for adult patients. This review provides an overview of appropriate measures for the safe perioperative care of patients, based on an understanding of the pathophysiological changes that occur in ES.

Role of endomyocardial biopsy for children presenting with acute systolic heart failure.

Myocarditis, an inflammatory disease of the heart, frequently results from viral infections, postviral immune-mediated responses, or both. It is a common cause of acute-onset systolic heart failure in children. Endomyocardial biopsy (EMB) remains the gold standard for the diagnosis of myocarditis. However, EMB is not performed for most myocarditis cases involving children in the United States. Clinical scenarios in which EMB results added unique prognostic data and guidance to therapy have been defined recently. This review outlines the role of EMB in the diagnosis and management of myocarditis for children presenting with acute-onset systolic heart failure.

Structure of the chemokine receptor CXCR1 in phospholipid bilayers.

CXCR1 is one of two high-affinity receptors for the CXC chemokine interleukin-8 (IL-8), a major mediator of immune and inflammatory responses implicated in many disorders, including tumour growth. IL-8, released in response to inflammatory stimuli, binds to the extracellular side of CXCR1. The ligand-activated intracellular signalling pathways result in neutrophil migration to the site of inflammation. CXCR1 is a class A, rhodopsin-like G-protein-coupled receptor (GPCR), the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors. Despite its importance, the molecular mechanism of CXCR1 signal transduction is poorly understood owing to the limited structural information available. Recent structural determination of GPCRs has advanced by modifying the receptors with stabilizing mutations, insertion of the protein T4 lysozyme and truncations of their amino acid sequences, as well as addition of stabilizing antibodies and small molecules that facilitate crystallization in cubic phase monoolein mixtures. The intracellular loops of GPCRs are crucial for G-protein interactions, and activation of CXCR1 involves both amino-terminal residues and extracellular loops. Our previous nuclear magnetic resonance studies indicate that IL-8 binding to the N-terminal residues is mediated by the membrane, underscoring the importance of the phospholipid bilayer for physiological activity. Here we report the three-dimensional structure of human CXCR1 determined by NMR spectroscopy. The receptor is in liquid crystalline phospholipid bilayers, without modification of its amino acid sequence and under physiological conditions. Features important for intracellular G-protein activation and signal transduction are revealed. The structure of human CXCR1 in a lipid bilayer should help to facilitate the discovery of new compounds that interact with GPCRs and combat diseases such as breast cancer.

Utility of impedance cardiography for the detection of hemodynamic changes in stable patients with sickle cell disease.

OBJECTIVES: The study sought to assess the potential utility of impedance cardiography (ICG) to detect hemodynamic changes after erythrocytapheresis in stable children with sickle cell disease (SCD). METHODS: We prospectively monitored cardiac index, systemic vascular resistance index, heart rate, and blood pressure using ICG before and after erythrocytapheresis in 26 stable children with SCD. Echocardiography was carried out in all patients to evaluate left ventricular systolic function. Hemoglobin (Hb), sickle cell hemoglobin (HbS), and ferritin levels were also measured. RESULTS: Of a total of 78 erythrocytapheresis procedures in 26 children with SCD, 22 (28.2%) had hypotensive episodes defined as a decrease in systolic, diastolic, or mean blood pressure by 10 mmHg. Risk factors for developing hypotension during erythrocytapheresis were identified with logistic regression analysis: lower-body surface area and decrease in cardiac index. In contrast, age, prepheresis Hb and HbS, serum ferritin levels, and left ventricular function at baseline were not associated with hypotension. CONCLUSIONS: This study demonstrates the feasibility of the ICG technique to detect the hemodynamic changes in children with SCD after an erythrocytapheresis procedure.

Clinical manifestations and long-term follow-up in pediatric patients living at altitude with isolated pulmonary artery of ductal origin.

This study's aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery (PA) of ductal origin (IPADO). This was a retrospective cohort study of 17 consecutive cases of IPADO at a single center. All patients lived at modest altitude (median 2050 m [range 1700 m to 3050 m]). Fifteen children (88%) were symptomatic at presentation. High-altitude pulmonary edema was present in 2 patients (12%) at diagnosis, and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up, and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with IPADO at modest altitude can potentially rehabilitate the isolated PA and reverse PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown.

Severe calcification of the aorta (porcelain aorta) associated with sarcoidosis in a pediatric heart transplant recipient.

We report a unique case of severe calcification of the aorta, bilateral coronary ostial stenoses and calcification of the mitral valve and left ventricle due to sarcoidosis. The patient underwent neonatal orthotopic heart transplantation secondary to hypoplastic left heart syndrome and developed hypercalcemia with other features of sarcoidosis at 10 yr of age. The mechanism for severe extra-renal calcification localized to the allograft is poorly understood, but may involve discordant local immune modulation and/or calcification-regulation between graft and host tissues.

(1)H-(13)C Hetero-nuclear dipole-dipole couplings of methyl groups in stationary and magic angle spinning solid-state NMR experiments of peptides and proteins.

(13)C NMR of isotopically labeled methyl groups has the potential to combine spectroscopic simplicity with ease of labeling for protein NMR studies. However, in most high resolution separated local field experiments, such as polarization inversion spin exchange at the magic angle (PISEMA), that are used to measure (1)H-(13)C hetero-nuclear dipolar couplings, the four-spin system of the methyl group presents complications. In this study, the properties of the (1)H-(13)C hetero-nuclear dipolar interactions of (13)C-labeled methyl groups are revealed through solid-state NMR experiments on a range of samples, including single crystals, stationary powders, and magic angle spinning of powders, of (13)C(3) labeled alanine alone and incorporated into a protein. The spectral simplifications resulting from proton detected local field (PDLF) experiments are shown to enhance resolution and simplify the interpretation of results on single crystals, magnetically aligned samples, and powders. The complementarity of stationary sample and magic angle spinning (MAS) measurements of dipolar couplings is demonstrated by applying polarization inversion spin exchange at the magic angle and magic angle spinning (PISEMAMAS) to unoriented samples.