Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

Outcomes Associated With Giant Coronary Artery Aneurysms After Kawasaki Disease: A Single-Center United States Experience.

OBJECTIVE: To determine the long-term outcomes among a cohort of patients with Kawasaki disease (KD) and a history of giant coronary artery aneurysms (CAA) at a single US center. RESULTS: There were 60 patients with KD and giant CAAs identified between 1989 and 2023. The majority of patients were male (71.7%) with median age at diagnosis of 0.9 years (0.2-13.3). Patients were followed for a median of 11 years, up to 34.5 years. MACE occurred in 13 (21.7%) patients at a median of 1.4 years (0.04-22.6) after KD diagnosis. The 10-, 20-, and 30-year MACE-free rates were 75%, 75%, and 60%. Patients with maximal CA z-scores ≥20 or bilateral CAA were more likely to have MACE. During follow-up, 26.7% of CAA regressed to normal luminal diameter at a median of 3.6 years (0.6-12.0). The 10-, 20- and 30-year likelihood of CA regression to normal luminal diameter was 36%, 46%, and 46%. CONCLUSIONS: Over 30 years, MACE occurred in nearly 22% of patients, more often in those with bilateral CAA or CA z-scores ≥20. Despite regression to normal luminal diameter in over 25% of CAA, patients with a history of KD-associated giant CAA require ongoing surveillance for cardiac complications, even years after the initial disease.

Adherence with lipid screening guidelines in standard- and high-risk children and adolescents.

Because atherosclerosis begins in childhood, universal lipid screening is recommended with special attention to conditions predisposing to early atherosclerosis. Data about real-world penetration of these guidelines is not available. METHODS: Retrospective cohort study using MarketScan® commercial and Medicaid insurance claims databases, a geographically representative sample of U.S. children. Subjects who passed through the 9- to 11-year window and had continuous insurance coverage between 1/1/2013 and 12/31/2016 were studied. Multivariable models were calculated, evaluating the association between other patient factors and the likelihood of screening. The primary hypothesis was that screening rates would be low, but that high-risk conditions would be associated with a higher likelihood of screening. RESULTS: In total, 572,522 children (51% male, 33% black, 11% Hispanic, 51% Medicaid) were studied. The prevalence of high-risk conditions was 2.2%. In unadjusted and adjusted analyses, these subjects were more likely to be screened than standard-risk subjects (47% vs. 20%, OR: 3.7, 95% CI 3.5-3.8, P < .001). Within this group, the diagnosis-specific likelihood of screening varied (26-69%). Endocrinopathies (OR 5.4, 95% CI 5.2-5.7), solid organ transplants (OR 5.0, 95% CI 3.8-6.6), and metabolic disease (OR 3.9, 95% CI 3.1-5.0, all P < .001) were associated with the highest likelihood of undergoing screening. CONCLUSIONS: Despite national recommendations, lipid screening was performed in a minority of children. Though subjects with high-risk conditions had a higher likelihood of screening, rates remained low. This study highlights the need for research and advocacy regarding obstacles to lipid screening of children in the United States.

Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents.

OBJECTIVES: To provide sex, age, and race specific reference values for ramp cycle ergometer cardiopulmonary exercise test (CPET) in children in the US. STUDY DESIGN: Retrospective review was conducted of all cardiopulmonary CPET data from our Exercise Physiology Laboratory on healthy children and adolescents (6-18 years) with body mass index between the 5th and 95th percentiles and structurally normal hearts who performed a ramp cycle ergometry stress test between 1999 and 2015. Twenty-eight exercise variables were included: peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, peak work rate, resting and peak heart rate and blood pressure, resting pulmonary function testing, and ventilatory responses to progressive exercise using breath-by-breath gas exchange. Owing to the nonlinear association between CPET results and age, fractional polynomials were used in the mixed-effects regression models to describe the sex- and age-specific normative values with 95% CIs, after adjusting for race and body mass index. RESULTS: We analyzed data on 1829 children (average age, 13.6 ± 2.6 years; 52% male). After 12 years of age, males generally had higher peak values for aerobic capacity and work rate. There were progressive increases with age for both sexes in resting pulmonary function and ventilatory response to exercise, peak aerobic and work rate, and oxygen pulse. Notably, there was an age-related decrease in ventilatory equivalents of oxygen and carbon dioxide at the ventilatory anaerobic threshold. CONCLUSIONS: Future research using prospective, inclusive, and statistically planned cohorts with standardized laboratory approaches and confirmed interoperability should be considered as a focus for validating normative pediatric CPET values in the future.

Anomalous aortic origin of a coronary artery: learning from the past to make advances in the future.

PURPOSE OF REVIEW: To review anomalous aortic origin of a coronary artery (AAOCA) anatomy, prevalence, mechanism and risk of ischemia, presentation, evaluation, management, and future directions. RECENT FINDINGS: Although most anatomic variants of AAOCA are benign, a small number are associated with increased risk of sudden death. A complete evaluation, including the use of advanced noninvasive imaging and provocative testing should be performed on nearly every patient with AAOCA. On the basis of recent studies, the ischemic risk appears to be greatest with a left anomalous coronary artery but an anomalous right coronary artery is not benign. Other risk factors include: a left anomalous coronary with an intramural course, high take-off, or slit-like orifice, and a right anomalous coronary with a longer intramural course. Exercise restriction is rarely recommended. Management primarily consists of nonoperative care, or surgical repair in those who are symptomatic or who have high-risk variants. Surgery itself continues to evolve; however, it is not benign, with a higher than expected chance of morbidity. SUMMARY: Advances have been made over the past decade regarding management of patients with AAOCA; however, the mechanism of ischemia and ability to predict risk is still incompletely understood. Management decisions should be based on anatomy, results of investigations, and shared decision-making with patients and their families. Surgery may be recommended for those at higher risk and should be done at centers experienced in AAOCA surgery. Future research should be collaborative in order to share experiences and insights to help advance our understanding of risk and ultimately to improve patient management.

Total anomalous origin of the coronary arteries from the pulmonary artery: a systematic review.

BACKGROUND: Although rare, coronary artery anomalies can have significant clinical implications. Total anomalous origin of the coronary arteries from the pulmonary artery (TCAPA) represents a rare subtype of coronary artery anomaly for which little is known. The aim of this review was to characterise the presentation, utilised diagnostic modalities, associated cardiac lesions, and treatment strategies in patients with TCAPA. METHODS: A systematic review was performed for cases of TCAPA using PubMed, Embase, and Web of Science. Keywords searched included "total anomalous origin of the coronary arteries from the pulmonary artery," "single ostium anomalous coronary artery from the pulmonary artery," and "anomalous origin of both coronary arteries from the pulmonary artery." RESULTS: Fifty-seven cases of TCAPA were identified in 50 manuscripts. Fifty-eight per cent of patients were male and the median age at presentation was 10 days (mean 1.71 ± 6.6 years, range 0 days-39 years). Most patients were symptomatic at the time of presentation; cyanosis (n = 22) and respiratory distress (n = 14) were the most common symptoms. Cases were most commonly diagnosed at autopsy (n = 26, 45.6%), but operative intervention was pursued in 22 cases (45.6%); aortic re-implantation (n = 14) and a Takeuchi-type repair (n = 7) were the most common routes of repair. CONCLUSIONS: The clinical presentation of patients with TCAPA was found to be variable, likely related to the presence of associated cardiac lesions. TCAPA should be considered in patients with suspected anomalous origin of the left coronary artery from the pulmonary artery for the serious consequences that can occur if not promptly corrected.

Severe hypertriglyceridemia associated with everolimus drug-eluting stent placement in an infant.

We report a case of severe hypertriglyceridemia associated with an everolimus drug-eluting stent in an infant with pulmonary vein stenosis. We review from current literature the mechanisms by which everolimus may cause dyslipidaemia, pharmacokinetics of everolimus in drug-eluting stents, and treatments of hypertriglyceridemia. This case demonstrates the need to closely monitor serum triglyceride levels after everolimus drug-eluting stent placement in infants.

Quality of life and exercise performance in unoperated children with anomalous aortic origin of a coronary artery from the opposite sinus of valsalva.

BACKGROUND: Anomalous aortic origin of a coronary artery is a congenital cardiac condition that can be associated with increased risk of sudden death. To date, quality of life and exercise performance have not been evaluated in patients with this condition who do not undergo surgical repair. METHODS: We carried out a cross-sectional analysis of patients with unoperated anomalous aortic origin of a coronary artery at our institution from 1 January, 2000 to 31 January, 2016. We prospectively assessed quality of life using standardised questionnaires. Medical records were reviewed for clinical and exercise stress test data. Statistical analyses were performed using Student's t-tests and Spearman's correlation coefficients. RESULTS: In total, 56 families completed the questionnaires. The average age at enrolment was 14.7±6 years. The majority were male (n=44, 78.6%) and had interarterial anomalous right coronary artery (n=38, 67.9%). Patients had normal quality of life on the PedsQL 4.0 Report, Child Health Questionnaire Child Form 87, and SF-36v2. Their parents had normal quality of life on the PedsQL 4.0 Parent Report, but parents of exercise-restricted patients had decreased Physical Functioning, General Health Perception, Emotional Impact on Parent, and Physical Summary scores (p<0.001-0.048) on the Child Health Questionnaire Parent Form 50. CONCLUSIONS: Patients with unoperated anomalous aortic origin of a coronary artery appear to have normal quality of life, but parents of exercise-restricted patients have decreased general health and emotional and physical quality of life scores. Improved counselling of families may be beneficial in this group. Future studies with more patients should evaluate quality of life and exercise performance over time.

Exercise restriction is not associated with increasing body mass index over time in patients with anomalous aortic origin of the coronary arteries.

Anomalous aortic origin of the coronary arteries is associated with exercise-induced ischaemia, leading some physicians to restrict exercise in patients with this condition. We sought to determine whether exercise restriction was associated with increasing body mass index over time. From 1998 to 2015, 440 patients ⩽30 years old were enrolled into an inception cohort. Exercise-restriction status was documented in 143 patients. Using linear mixed model repeated-measures regression, factors associated with increasing body mass index z-score over time, including exercise restriction and surgical intervention as time-varying covariates, were investigated. The 143 patients attended 558 clinic visits for which exercise-restriction status was recorded. The mean number of clinic visits per patient was 4, and the median duration of follow-up was 1.7 years (interquartile range (IQR) 0.5-4.4). The median age at first clinic visit was 10.3 years (IQR 7.1-13.9), and 71% (101/143) were males. All patients were alive at their most recent follow-up. At the first clinic visit, 54% (78/143) were exercise restricted, and restriction status changed in 34% (48/143) during follow-up. The median baseline body mass index z-score was 0.2 (IQR 0.3-0.9). In repeated-measures analysis, neither time-related exercise restriction nor its interaction with time was associated with increasing body mass index z-score. Surgical intervention and its interaction with time were associated with decreasing body mass index z-score. Although exercise restriction was not associated with increasing body mass index over time, surgical intervention was associated with decreasing body mass index z-score over time in patients with anomalous aortic origin of the coronary arteries.

Coronary artery anomalies in children: what is the risk?

PURPOSE OF REVIEW: To better understand the risk of sudden death from coronary anomalies. RECENT FINDINGS: Most coronary anomalies are benign, but there are certain coronary anomalies that increase the risk of sudden cardiac death (SCD) in the young, notably anomalous aortic origin of a coronary artery from the wrong sinus. Previously, the risk of SCD attributed to certain coronary anomalies was felt to be quite high, as the risk assessment was based on autopsy series. Recent studies have shown that the risk attributed to anomalous coronary arteries is much lower than once believed. Risk appears to be highest with anomalous left coronary artery from the right sinus of Valsalva with interarterial course, notably when the young patient is participating in vigorous physical exertion, such as with competitive sports. SUMMARY: Treatment strategies may include exercise restriction or surgical repair. Management decisions should be based on a complete understanding of the risk for SCD because of anomalous coronary arteries. Future directions should focus on better methods to risk stratify these pediatric patients.

What is this chocolate milk in my circuit? A cause of acute clotting of a continuous renal replacement circuit: Questions.

INTRODUCTION: One of the greatest problems associated with continuous renal replacement therapy (CRRT) is the early clotting of filters. A literature search revealed three case reports of lipemic blood causing recurrent clotting and reduced CRRT circuit survival time in adult patients, but no reports of cases in children. DIAGNOSIS/TREATMENT: A 23-month-old male infant with Martinez-Frias syndrome and multivisceral transplant was admitted to the hospital with severe sepsis and hemolytic anemia. He developed acute kidney injury, fluid overload and electrolyte imbalances requiring CRRT and was also administered total parenteral nutrition (TPN) and fat emulsion. The first circuit lasted 60 h before routine change was required. The second circuit showed acute clotting after only 18 h, and brownish-milky fluid was found in the circuit tubing layered between the clotted blood. The patient's serum triglyceride levels were elevated at 988 mg/dL. The lipid infusion was stopped and CRRT restarted. Serum triglyceride levels improved to 363 mg/dL. The new circuit lasted 63 h before routine change was required. CONCLUSION: Clotting of CRRT circuits due to elevated triglyceride levels is rare and has not been reported in the pediatric population. Physicians should be mindful of this risk in patients receiving TPN who have unexpected clotting of CRRT circuits.

Cardiac MRI and CT: differentiation of normal ostium and intraseptal course from slitlike ostium and interarterial course in anomalous left coronary artery in children.

OBJECTIVE: Anomalous left coronary artery from the inappropriate aortic sinus with intraseptal course is generally benign but can be confused on imaging studies with the potentially lethal interarterial, intramural anomalous left coronary artery. The purpose of this study was to assess normal ostial morphologic features and intraseptal course using cardiac MRI and CT in pediatric patients with intraseptal anomalous left coronary artery. MATERIALS AND METHODS: A retrospective review was conducted of the medical records of 14 children with the diagnosis of intraseptal anomalous left coronary artery between November 2009 and March 2013. Coronary artery origin and course were evaluated with cardiac MRI or CT, and 3D assessment of coronary ostial morphologic features was performed with virtual angioscopy. RESULTS: The patient ages ranged from 5 to 18 years at diagnosis; 10 (71.4%) were boys. The right and left coronary origins were the right sinus of Valsalva as a common origin (n = 9) or a single coronary artery (n = 5). Anomalous intraseptal left main coronary was found in 13 patients, and one patient had anomalous left anterior descending with retroaortic circumflex coronary artery. Anomalous coronary ostia were round and without stenosis in all studies. The anomalous vessel was identified with echocardiography, but the anomalous left coronary artery was not delineated, and a normal ostium was not adequately portrayed in any instance. CONCLUSION: By use of cardiac MRI and CT, the anomalous course of round coronary ostia was confirmed and visualized in a pediatric cohort with intraseptal anomalous left coronary artery. The data provide the basis for understanding the benign clinical course and showing that surgery is unnecessary for this coronary anomaly.

Primary-care management of patients with congenital anomalies of the coronary arteries.

Congenital anomalies of the coronary arteries, although uncommon, have the potential to cause serious myocardial damage, ischaemic cardiomyopathy, and sudden cardiac death. This article summarises aspects of care for these patients in the outpatient setting, including clinical history and physical examination findings, ancillary testing, decision-making regarding the need for surgical intervention, and recommendations for physical activity. Although there are limited data regarding some of these recommendations, it is hoped that these can be used as an initial benchmark against which further data will lead to a more evidence-based approach.

The Congenital Heart Surgeons' Society Registry of Anomalous Aortic Origin of a Coronary Artery: an update.

The anomalous aortic origin of a coronary artery from the wrong sinus of Valsalva with an interarterial, intramural, and/or intraconal course is a relatively rare congenital defect of the heart that may be associated with an increased risk of ischaemia of the myocardium and sudden death, notably in children and young adults. Data are limited regarding stratification of risk and long-term outcomes of these patients. In 2009, the Anomalous Coronary Artery Working Group formed the Congenital Heart Surgeons' Society Registry of Anomalous Aortic Origin of a Coronary Artery to obtain information on large numbers of young patients with anomalous aortic origin of a coronary artery with the goal to better understand the natural and surgical history of this anomaly as well as to develop evidence-based treatment and management guidelines. In this report, we describe the data we have collected from the registry and the current state of the registry.

Anomalous Aortic Origin of a Coronary Artery.

BACKGROUND: Although anomalous aortic origin of a coronary artery (AAOCA) is associated with risk of sudden cardiac arrest (SCA), there is a spectrum of disease, with the appropriate management for many remaining unclear. Increasing data warrant review for an updated perspective on management. METHODS: A panel of congenital cardiac surgeons, cardiologists, and imaging practitioners reviewed the current literature related to AAOCA and its management. Survey of relevant publications from 2010 to the present in PubMed was performed. RESULTS: The prevalence of AAOCA is 0.4% to 0.8%. Anomalous left coronary artery is 3 to 8 times less common than anomalous right coronary, but carries a much higher risk of SCA. Nevertheless, anomalous right coronary is not completely benign; 10% demonstrate ischemia, and it remains an important cause of SCA. Decision-making regarding which patients should be recommended for surgical intervention includes determining anatomic features associated with ischemia, evidence of ischemia on provocative testing, and concerning cardiovascular symptoms. Ischemia testing continues to prove challenging with low sensitivity and specificity, but the utility of new modalities is an active area of research. Surgical interventions focus on creating an unobstructed path for blood flow and choosing the appropriate surgical technique given the anatomy to accomplish this. Nontrivial morbidity has been reported with surgery, including new-onset ischemia. CONCLUSIONS: A proportion of patients with AAOCA demonstrate features and ischemia that warrant surgical intervention. Continued work remains to improve the ability to detect inducible ischemia, to risk stratify these patients, and to provide guidance in terms of which patients warrant surgical intervention.

Fatness is not a factor of fitness: analysis of cardiorespiratory data from healthy children over an 8-year period.

PURPOSE: To evaluate exercise performance and body mass index in healthy children over an 8-year period in order to determine whether cardiorespiratory fitness has decreased relative to changes in body mass index in our patient population. METHOD: This study is a retrospective review of anthropometric and cardiorespiratory fitness data from our hospital's Exercise Physiology Laboratory's database on 1201 healthy children (6-18 years) with structurally normal hearts who performed one cycle ergometry test between 1999 and 2006. Subjects were stratified by gender and age. Body mass index was compared between 1999-2002 (Early Group) and 2003-2006 (Late Group) and with national averages. Exercise outcome variables were maximal oxygen consumption, anaerobic threshold, physical working capacity indexed to body weight. Analysis of variance was used to detect differences between groups for each outcome variable. RESULTS: Body mass index was not significantly different from national data (p-value equals 0.79) or between groups. A negative trend (p-value greater than 0.15 less than 0.20) was observed among most indices of exercise performance between Early and Late Groups. Significantly lower anaerobic threshold was found among males between Early and Late Group (25.7 plus or minus 0.9 versus 23.4 plus or minus 1.6 millilitres per kilogram per minute, p-value less than 0.01), and in physical working capacity among females between Early and Late Groups (2.9 plus or minus 0.1 versus 2.7 plus or minus 0.1, p-value less than 0.05). CONCLUSIONS: Cardiorespiratory fitness in males and working capacity in females declined over time independent of body mass index. This suggests that other measures may need to be evaluated for promotion of overall cardiovascular health.

Adherence With Lipid Screening Guidelines in Children With Acquired and Congenital Heart Disease: An Observational Study Using Data From The MarketScan Commercial and Medicaid Databases.

Background Universal lipid screening in children provides an opportunity to mitigate the lifetime risk of atherosclerosis, particularly in children with chronic conditions that are predisposed to early atherosclerosis. In response, national guidelines recommend additional early screening in a subset of cardiac conditions. The penetration of such guidelines has not been evaluated. Methods and Results We performed a retrospective study of a geographically representative sample of US children using the MarketScan Commercial and Medicaid claims databases. The study population was children with cardiac disease between ages 2 and 18 years and ≥3 years of continuous coverage from January 1, 2013, to June 30, 2018, divided into 4 major strata of heart disease. We assessed the likelihood of screening between these classifications and compared with healthy children and calculated multivariate models to identify patient factors associated with screening likelihood. Of the eligible 8.4 million children, 155 000 children had heart disease, of which 1.8% (31 216) had high-risk conditions. Only 17.5% of healthy children underwent lipid screening. High-risk children were more likely to be screened (odds ratio [OR], 2.1; 95% CI, 2.09-2.19; P<0.001) than standard-risk children, but that likelihood varied depending on strata of cardiac disease (22%-77%). Timing of screening also varied, with most occurring between ages 9 and 11 years. Among cardiac conditions, heart transplantation (OR, 16.8; 95% CI, 14.4-19.7) and cardiomyopathy (OR, 2.9; 95% CI, 2.8-3.1) were associated with the highest likelihood of screening. Conclusions Children with cardiac disease are more likely to undergo recommended lipid screening than healthy children, but at lower rates and later ages than recommended, highlighting the importance of quality improvement and advocacy for this vulnerable population.

Anomalous aortic origin of a coronary artery in siblings with Marfan syndrome.

We report a case of two brothers with Marfan syndrome and coexistent anomalous aortic origin of a coronary artery from the wrong sinus of Valsalva. To our knowledge, this is the first ever report of siblings with Marfan syndrome who also have anomalous aortic origin of a coronary artery. The treatment and management options in the context of sudden death risk are discussed.

Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.

A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism.