Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

Emergence of innovations in networked populations with reputation-driven interactions.

In this work, we analyze how reputation-based interactions influence the emergence of innovations. To do so, we make use of a dynamic model that mimics the discovery process by which, at each time step, a pair of individuals meet and merge their knowledge to eventually result in a novel technology of higher value. The way in which these pairs are brought together is found to be crucial for achieving the highest technological level. Our results show that when the influence of reputation is weak or moderate, it induces an acceleration of the discovery process with respect to the neutral case (purely random coupling). However, an excess of reputation is clearly detrimental, because it leads to an excessive concentration of knowledge in a small set of people, which prevents a diversification of the technologies discovered and, in addition, leads to societies in which a majority of individuals lack technical capabilities.

Longitudinal effect of disease-modifying therapy on left ventricular diastolic function in children with sickle cell anemia.

Cardiac abnormalities seen in sickle cell anemia (SCA) include diastolic dysfunction, which has been shown to be associated with high morbidity and early mortality. The effect of disease-modifying therapies (DMT) on diastolic dysfunction is poorly understood. We prospectively evaluated the effects of hydroxyurea and monthly erythrocyte transfusions on diastolic function parameters over 2 years. A total of 204 subjects with HbSS or HbSß0-thalassemia (mean age 11 ± 3.7 years), unselected for disease severity, had diastolic function assessed with surveillance echocardiograms twice, 2 years apart. During this 2-year observation period, 112 participants received DMTs (hydroxyurea, n = 72, monthly erythrocyte transfusions, n = 40), 34 initiated hydroxyurea, and 58 did not receive any DMT. The entire cohort showed an increase in left atrial volume index (LAVi) of 3.40 ± 10.86 mL/m2, p = .001 over 2 years. This increase in LAVi was independently associated with anemia, high baseline E/e' or LV dilation. Individuals not exposed to DMT were younger (mean age 8.8 ± 2.9 years), but at baseline their prevalence of abnormal diastolic parameters was similar to that of the DMT-exposed participants who were older (mean age 12 ± 3.8 years). Participants on DMTs saw no improvement in diastolic function over the study period. In fact, participants on hydroxyurea saw a possible worsening in diastolic parameters (14% increase in LAVi and ~5% decrease in septal e') but also a ~9% decrease in fetal hemoglobin (HbF) levels. Further studies are needed to evaluate if exposure to DMT for a longer duration or achieving higher HbF might be beneficial in alleviating diastolic dysfunction.

Computational Structural Revision of Elaeophorbate and Other Triterpenoids with the Help of NAPROC-13. A New Strategy for Structural Revision of Natural Products.

A considerable number of natural products have been published in recent years with misassigned structure, even though they had been correctly elucidated in the past. The availability of databases containing revised structures can prevent the amplification of errors in structural elucidation. NAPROC-13, a dereplication tool based on the 13C chemical shift, has been used to search for substances that, possessing the same chemical shifts, have been described with different structures. The correct structure of these different structural proposals is verified by computational chemistry. This paper reports the structural revision of nine triterpenoids following this methodology.

Synergistic Combination of NAPROC-13 and NMR 13C DFT Calculations: A Powerful Approach for Revising the Structure of Natural Products.

This article describes the structure revision of nine triterpenoids that have been reported corresponding to the same 13C NMR data set. In addition, 13C NMR calculation shows that some chemical shift assignments must be swapped. Our analysis improves the fit between the experimental and calculated data. Correcting misassigned structures and correctly assigning each signal is essential for elucidating new structurally related compounds. Furthermore, the ambiguity of several compounds, the structure of which differs in the literature and the Sci-Finder database, has been eliminated. Misassigned structures were found by chemical shift searches in NAPROC-13, and the results provide two or more different compounds with the same 13C NMR data. The process to determine the correct, most likely structural proposal in agreement with the experimental 13C NMR data was carried out by DFT calculations.

Biomarker sST2 in Adults with Transposition of the Great Arteries Palliated by Mustard Procedure: A Five-Year Follow-up.

The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49 years, mean of 35.8 vs. mean 32.6 years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality.

Clinical approach to antibody-mediated rejection from the pediatric heart transplant society.

OBJECTIVE: This document is designed to outline the definition, pathogenesis, diagnostic modalities and therapeutic measures to treat antibody-mediated rejection in children postheart transplant METHODS: Literature review was conducted by a Pediatric Heart Transplant Society (PHTS) working group to identify existing pediatric and adult studies on antibody-mediated rejection (AMR). In addition, the centers participating in PHTS were asked to submit their approach to diagnosis and management of pediatric AMR. This document synthesizes information gathered from both these sources to highlight a practical approach to diagnosing and managing a child with AMR postheart transplant. This document may not represent the practice at all centers in the PHTS and serves as a starting point to understand an approach to this clinical scenario.

Current Practices in Treating Cardiomyopathy and Heart Failure in Duchenne Muscular Dystrophy (DMD): Understanding Care Practices in Order to Optimize DMD Heart Failure Through ACTION.

Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies.

Cardiac remodeling after anthracycline and radiotherapy exposure in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study.

BACKGROUND: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy. METHODS: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed. RESULTS: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15-2.68). CONCLUSIONS: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance.

Antithymocyte globulin induction therapy and myocardial complement deposition in pediatric heart transplantation.

BACKGROUND: Antithymocyte globulin (ATG) consists of polyclonal antibodies directed primarily against human T lymphocytes but may contain antibodies with affinity for other tissues in the transplanted organ, resulting in complement (C4d) deposition. This phenomenon has been demonstrated in endomyocardial biopsies (EMBs) of adult cardiac transplants. We examined the relationship of induction immunosuppression with ATG and C4d deposition in EMB of pediatric cardiac transplants. METHODS: Results of C4d immunohistochemistry were available from all EMB of patients transplanted at our center between June 2012 and April 2018 (n = 48) who received induction immunosuppression with either ATG (n = 20) or basiliximab (n = 28) as the standard of care. RESULTS: C4d deposition in the first year post-heart transplant was more commonly seen among patients who received ATG induction (20% of EMBs in ATG group vs 1% of EMBs in basiliximab group; p < .0001). C4d deposition related to ATG was observed early post-transplant (50% ATG vs 0% basiliximab on first EMB; p < .0001 and 35% ATG vs 0% basiliximab on the second EMB; p = .0012). While this difference waned by the third EMB (5% ATG vs 0% basiliximab; p = .41), positive C4d staining persisted to the sixth EMB in the ATG group only (6%). CONCLUSION: C4d deposition is common on EMB up to 1 year post-pediatric cardiac transplant following ATG induction. This high rate of positive C4d staining in the absence of histologic AMR after ATG induction therapy must be accounted for in making clinical decisions regarding cardiac allograft rejection diagnosis and treatment.

Novel use of cangrelor in pediatrics: A pilot cohort study demonstrating use in ventricular assist devices.

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end-stage heart failure and VAD circulation. Additionally, 20%-40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short-acting, reversible, intravenous P2Y12 platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single-center review of patients admitted to a tertiary medical center with end-stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y12 < 180 platelet reaction units (PRU), was measured with serial point-of-care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5-103). The median duration on cangrelor was 43 days (IQR 8-70). The median cangrelor dose to reach the therapeutic threshold was 0.75 µg/kg/min with the mean P2Y12 , while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long-term use of cangrelor in pediatric patients. The reversibility and short half-life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.

Phase-unwrapping method based on local polynomial models and a maximum a posteriori model correction.

Recently, a theory on local polynomial approximations for phase-unwrapping algorithms, considering a state space analysis, has been proposed in Appl. Opt.56, 29 (2017)APOPAI0003-693510.1364/AO.56.000029. Although this work is a suitable methodology to deal with relatively low signal to noise ratios observed in the wrapped phase, the methodology has been developed only for local-polynomial phase models of order 1. The resultant proposal is an interesting Kalman filter approach for estimating the coefficient or state vectors of these local plane models. Thus, motivated by this approach and simple Bayesian theory, and considering our previous research on local polynomial models up to the third order [Appl. Opt.58, 436 (2019)APOPAI0003-693510.1364/AO.58.000436], we propose an equivalent methodology based on a simple maximum a posteriori estimation, but considering a different state space: difference vectors of coefficients for the current high-order polynomial models. Specific estimations of the covariance matrices for difference vectors, as well as noise covariance matrices involved with the correct estimation of coefficient vectors, are proposed and reconstructions with synthetic and real data are provided.

Arteriovenous Fistula after Endovenous Laser Ablation of Great Saphenous Vein Treated with Covered Stent: Case Report and Literature Review.

Endovenous ablation techniques (radiofrequency or laser) have become the less invasive choice of treatment for superficial venous insufficiency due to saphenous vein incompetence showing high effectiveness and few complications. We present a case of symptomatic arteriovenous fistula between the external iliac artery and vein after endovenous laser ablation repaired with covered stent. We also review the literature and discuss the possible causes and management of this unusual and potentially severe complication, and the feasibility of endovascular treatment.

Secondary Ablation of Recanalized Saphenous Vein after Endovenous Thermal Ablation.

BACKGROUND: To describe the occlusion rate and clinical response of a redo ablative procedure in symptomatic patients with recanalization of saphenous vein after endovascular thermal ablation. METHODS: A retrospective cohort study was performed in a prospectively collected data of symptomatic patients with recanalization of the great saphenous vein (GSV) or small saphenous vein (SSV) after endovascular thermal ablation who underwent a secondary ablation (SA) from June 2015 to May 2018. RESULTS: Ten patients (15 limbs) with recanalization of the GSV or SSV were treated with SA. The median age was 67 years and 60% were men. The median time from the first ablation was 7.3 years (interquartile range [IQR] 6.5-9.6). For SA, radiofrequency ablation was performed in 12 limbs (80%) and ultrasound-guided foam sclerotherapy in 3 cases (20%). The GSV was the treated vessel in 14 cases (93.3%). No complications were reported. Median follow-up was 13 months. Preoperative and 1-year follow-up Venous Clinical Severity Score was 9 (IQR 5-10) and 4 (IQR 2-8), respectively. Duplex ultrasound evaluation after 1 year showed an occlusion rate of 93.3% evidencing a partially recanalized vein in 1 treated limb. CONCLUSIONS: In this study, the occlusion rate was 93.3% at 1 year after SA; clinical improvement and no complications were reported. SA appears to be a valid option for the treatment of symptomatic patients with recanalized GSV or SSV.

Conservative management of knee arthropathy in a patient with Klippel Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare vascular malformation characterized by capillary malformation, venous malformations, and soft tissue or bone hypertrophy that affect the extremities in most cases. Knee or hip arthropathy are common associated conditions and cause serious disability. We present the case of a patient with a diagnosis of KTS and severe knee arthropathy. A 34-year-old man with KTS was referred to our hospital with severe knee arthropathy, with the joint fixed in a 90° position. CT Angiography and MRI of the left leg showed important varicose development of the superficial venous system with intraarticular vessels. After discussion of the case by a multidisciplinary committee, the patient was enrolled on a physiotherapy program and had achieved significant improvements in movement and quality of life at 12-month follow-up. Treatment of KTS is primarily conservative and a multidisciplinary approach is necessary.

A síndrome de Klippel-Trenaunay (SKT) é uma malformação vascular rara caracterizada por malformação capilar, malformações venosas e hipertrofia de tecidos moles ou ósseos que afetam as extremidades na maioria dos casos. A artropatia do joelho ou do quadril é uma condição comumente associada e causa sérias deficiências. Apresentamos o caso de um paciente com diagnóstico de SKT e artropatia grave do joelho. Um homem de 34 anos com SKT foi encaminhado ao nosso hospital com artropatia grave do joelho com articulação fixa na posição de 90 °. A angiotomografia e a ressonância magnética da perna esquerda mostraram importante desenvolvimento varicoso do sistema venoso superficial com vasos intra-articulares. Após o caso ser discutido em um comitê multidisciplinar, o paciente foi incluído em um programa de fisioterapia, obtendo uma melhora significativa nos movimentos e na qualidade de vida após 12 meses de acompanhamento. O tratamento da SKT é principalmente conservador e exige uma abordagem multidisciplinar.

Identifiable Risk Factors and Miscalculations During Listing for Pediatric Heart Transplantation.

The objective of this study is to describe identifiable risk factors, complications, and pitfalls while listing pediatric patients for heart transplantation, which is the standard of care for end-stage heart disease in children. Since the introduction of cyclosporine in the 1980s, the management in pediatric heart transplantation has shown consistent improvement, mainly because of technological advances and the integration of multidisciplinary teams in the field. However, the complexity of this patient population makes medical providers vulnerable to complications as a result of undesirable mistakes. Transplant survival is impacted negatively when mistakes from health-care providers compound the high-risk status of the patient. The identification of multiple risk factors and undesirable miscalculations may help transplant teams make decisions before allocating organs, intervene or minimize morbidity, and provide the best quality of life to recipients.

Noncompaction cardiomyopathy and heterotaxy syndrome.

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by compact and trabecular layers of the left ventricular myocardium. This cardiomyopathy may occur with congenital heart disease (CHD). Single cases document co-occurrence of LVNC and heterotaxy, but no data exist regarding the prevalence of this association. This study sought to determine whether a non-random association of LVNC and heterotaxy exists by evaluating the prevalence of LVNC in patients with heterotaxy. In a retrospective review of the Indiana Network for Patient Care, we identified 172 patients with heterotaxy (69 male, 103 female). Echocardiography and cardiac magnetic resonance imaging results were independently reviewed by two cardiologists to ensure reproducibility of LVNC. A total of 13/172 (7.5%) patients met imaging criteria for LVNC. The CHD identified in this subgroup included atrioventricular septal defects [11], dextrocardia [10], systemic and pulmonary venous return abnormalities [7], and transposition of the great arteries [5]. From this subgroup, 61% (n = 8) of the patients developed arrhythmias; and 61% (n = 8) required medical management for chronic heart failure. This study indicates that LVNC has increased prevalence among patients with heterotaxy when compared to the general population (0.014-1.3%) suggesting possible common genetic mechanisms. Interestingly, mice with a loss of function of Scrib or Vangl2 genes showed abnormal compaction of the ventricles, anomalies in cardiac looping, and septation defects in previous studies. Recognition of the association between LVNC and heterotaxy is important for various reasons. First, the increased risk of arrhythmias demonstrated in our population. Secondly, theoretical risk of thromboembolic events remains in any LVNC population. Finally, many patients with heterotaxy undergo cardiac surgery (corrective and palliative) and when this is associated with LVNC, patients should be presumed to incur a higher peri-operative morbidity based on previous studies. Further research will continue to determine long-term and to corroborate genetic pathways.

Endovascular radiofrequency ablation. Effect on the vein diameter using the ClosureFast(®) catheter. / Ablación endovascular por radiofrecuencia. Efecto sobre el diámetro venoso con el uso del catéter ClosureFast(®).

INTRODUCTION: Endovascular radiofrequency with first generation catheters was not successful due to its technical difficulty and restrictions in veins with diameters larger than 12mm. However, using the new catheter there is not enough scientific evidence to affirm that the diameter represents a technical limitation. The aim of this study was to evaluate and compare pre and post-operative venous trunks diameter, aiming at the reduction of size after 6 months with last generation catheters. METHODS: Retrospective observational and descriptive study on a cohort of patients with insufficiency of the great saphenous vein, small saphenous vein and anterior accessory vein operated on with last generation radiofrequency catheters. The diameters were evaluated in the pre and post-operative period with ultrasound. RESULTS: Between 2007 and 2014 a total of 365 ablations were performed in veins with an average diameter of 9±3.1mm showing a reduction of it after 6 months with a mean value of 5.2±0.8mm (P<.0001). Total occlusion was also observed in 100% of cases and complications such as deep vein thrombosis in 0.5% and heat-induced thrombosis in 1.1%. CONCLUSIONS: A significant reduction in venous diameter after endovascular treatment with the new ClosureFast(®) catheters was checked, even in veins with diameters greater than 12mm.