Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS: In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS: Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION: Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.

Haemodynamic effects of prophylactic post-operative hydrocortisone following cardiopulmonary bypass in neonates undergoing cardiac surgery.

Multiple studies have endeavoured to define the role of steroids in paediatric congenital heart surgery; however, steroid utilisation remains haphazard. In September, 2017, our institution implemented a protocol requiring that all neonates undergoing cardiac surgery with the use of cardiopulmonary bypass receive a five-day post-operative hydrocortisone taper. This single-centre retrospective study was designed to test the hypothesis that routine post-operative hydrocortisone administration reduces the incidence of capillary leak syndrome, leads to favourable postoperative fluid balance, and less inotropic support in the early post-operative period. Data were gathered on all term neonates who underwent cardiac surgery with the use of bypass between September, 2015 and 2019. Subjects who were unable to separate from bypass, required long-term dialysis, or long-term mechanical ventilation were excluded. Seventy-five patients met eligibility criteria (non-hydrocortisone group = 52; hydrocortisone group = 23). For post-operative days 0-4, we did not observe a significant difference in net fluid balance or vasoactive inotropic score between study groups. Similarly, we saw no major difference in secondary clinical outcomes (post-operative duration of mechanical ventilation, ICU/hospital length of stay, and time from surgery to initiation of enteral feeds). In contrast to prior analyses, our study was unable to demonstrate a significant difference in net fluid balance or vasoactive inotropic score with the administration of a tapered post-operative hydrocortisone regimen. Similarly, we saw no effect on secondary clinical outcomes. Further long-term randomised control studies are necessary to validate the potential clinical benefit of utilising steroids in paediatric cardiac surgery, especially in the more fragile neonatal population.

Clinical and Laboratory Correlates of QTc Duration in Adult and Pediatric Sickle Cell Disease.

Background: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia. Methods: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration. Results: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds. Conclusion: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community.

Pediatric Extracorporeal Membrane Oxygenation Anticoagulation Protocol Associated with a Decrease in Complications.

Extracorporeal membrane oxygenation (ECMO) in pediatrics has rapidly progressed in recent years; however, there continues to be considerable variation in anticoagulation practices. In 2016, we implemented a standardized anticoagulation protocol in effort to reduce clotting and bleeding complications. A single-center retrospective analysis of pediatric patients requiring ECMO between 2014 and 2018 was performed. One hundred one ECMO cases in 94 pediatric patients met eligibility criteria (preprotocol = 64 cases; postprotocol = 37 cases). Demographics, ECMO parameters, complications, laboratories, and blood product requirements were analyzed for differences between the two groups. There was a significant decrease in the incidence of hematologic (p < 0.022), neurologic (p < 0.001), and renal complications (p < 0.001) in the postprotocol era. Incidence of bleeding, cardiac/pulmonary complications, and circuit changes were similar between the groups. The postprotocol group required fewer transfusions of red blood cells and cryoprecipitate. Additionally, platelet counts and fibrinogen levels were maintained higher in the postprotocol era. In conclusion, implementation of a standardized anticoagulation protocol was associated with improved anticoagulation parameters and a decrease in hematologic and neurologic complications, coagulopathy, renal injury, and blood product administration. We attribute these findings to transitioning to anti-Xa as a measure of heparinization and maintaining higher platelet counts.

Two rare cases of paraganglioma in patients with Fontan physiology.

Pheochromocytoma/paraganglioma is an exceedingly rare tumour, thought to share an association with cyanotic CHD. This association is thought to be a result of chronic hypoxaemia (Antonio et al, Revista Española de Cardiología (English Edition) 2017; 70: 673-675; Folger et al, Circulation 1964; 29: 750-757; Opotowsky et al, J Clin Endocrinol Metab 2015; 100: 1325-1334) We report two cases of paraganglioma over a 4-year period in patients with hypoplastic left heart syndrome who had undergone Fontan completion by ages 2 and 4. Based on a very small number of reported cases of CHD, the mechanism of tumourigenesis is unclear. It is imperative that cases associated with CHD continue to be reported so that we may learn more about the pathogenesis and epidemiology of this entity.

Obesity and Diabetes Mellitus Adversely Affect Outcomes after Cardiac Surgery in Children's Hospitals.

OBJECTIVE: To assess how obesity or diabetes mellitus impacts outcomes in patients undergoing cardiac surgery in pediatric hospitals. DESIGN: A multi-institutional, matched case-control study of the Pediatric Health Information System database was performed. SETTING: Tertiary children's hospitals in the United States. PATIENTS: All cardiac surgical cases in patients with obesity or diabetes mellitus between 2004 and 2012 were included. Cases were matched to controls by age, sex, race, and Risk Adjustment for Congenital Heart Surgery score. OUTCOME MEASURES: Mortality, surgical complications, and hospital utilization. Differences in outcome measures were assessed by chi-square and Mann-Whitney tests. P value < .05 was significant. RESULTS: Six hundred twenty-nine cardiac surgical cases (median age 17 years [IQR 12-32]) with obesity or diabetes mellitus were matched to 629 controls. Cases demonstrated lower median household income than those in the control group ($38,031 [IQR $31,900-$48,844] vs. ($41,896 [IQR $32,854-$56,020], P < .001). Mortality was similar between cases and controls (22% vs. 1.9%, P =.692). Surgical complications occurred similarly between cases and controls (13.5% vs. 12.4%, P = .535). Cases had longer intensive care unit length of stay than controls (3 vs. 2 days, P = .001), resulting in longer overall hospital length of stay (5 vs. 4 days, P < .001). Cases also had a higher odds of undergoing mechanical ventilation for >96 hours (OR 2.0, 95% CI 1.1-3.7) and higher rate of total parenteral nutrition use (7.2% vs. 4.5%, P = .040). Median hospital charges were higher in cases (clinical: $6,696 vs. $5,872; laboratory: $14,168 vs. $12,251; pharmacy: $12,971 vs. $10,426; imaging: $6,259 vs. $5,660; P ≤ .030 for all). CONCLUSIONS: The presence of obesity or diabetes mellitus was associated with increased postoperative morbidity, hospital utilization, and cost in patients undergoing cardiac surgery in pediatric hospitals.

Isolated Left Subclavian Artery From the Pulmonary Artery Masked by Pulmonary Hypertension.

Isolated subclavian artery arising from the pulmonary artery is exceedingly rare. Most cases are associated with other forms of congenital heart disease and typically present with subclavian or pulmonary steal syndromes. We report the case of a patient with pulmonary hypertension which masked the isolated subclavian artery, allowing it to masquerade as another common congenital heart lesion.

The Pathophysiology of Heart Failure in Children: The Basics.

Few data exist on the pathophysiologic changes in pediatric heart failure. Most of the knowledge has evolved from animal models of ischemic or idiopathic dilated cardiomyopathy. This review addresses the pathophysiologic changes that occur in the failing heart from animal models and the adult experience to unique aspects of heart failure in children.

Alternative strategies in newborns and infants with major co-morbidities to improve congenital heart surgery outcomes at an emerging programme.

INTRODUCTION: Debilitating patient-related non-cardiac co-morbidity cumulatively increases risk for congenital heart surgery. At our emerging programme, flexible surgical strategies were used in high-risk neonates and infants generally considered in-operable, in an attempt to make them surgical candidates and achieve excellent outcomes. MATERIALS AND METHODS: Between April, 2010 and November, 2013, all referred neonates (142) and infants (300) (average scores: RACHS 2.8 and STAT 3.0) underwent 442 primary cardiac operations: patients with bi-ventricular lesions underwent standard (n=294) or alternative (n=19) repair/staging strategies, such as pulmonary artery banding(s), ductal stenting, right outflow patching, etc. Patients with uni-ventricular hearts followed standard (n=96) or alternative hybrid (n=34) staging. The impact of major pre-operative risk factors (37%), standard or alternative surgical strategy, prematurity (50%), gestational age, low birth weight, genetic syndromes (23%), and major non-cardiac co-morbidity requiring same admission surgery (27%) was analysed on the need for extracorporeal membrane oxygenation, mortality, length of intubation, as well as ICU and hospital length of stays. RESULTS: The need for extracorporeal membrane oxygenation (8%) and hospital survival (94%) varied significantly between surgical strategy groups (p=0.0083 and 0.028, respectively). In high-risk patients, alternative bi- and uni-ventricular strategies minimised mortality, but were associated with prolonged intubation and ICU stay. Major pre-operative risk factors and lower weight at surgery significantly correlated with prolonged intubation, hospital length of stay, and mortality. DISCUSSION: In our emerging programme, flexible surgical strategies were offered to 53/442 high-risk neonates and infants with complex CHDs and significant non-cardiac co-morbidity, in order to buffer risk and achieve patient survival, although at the cost of increased resource utilisation.

Chondrosarcoma presenting with pulmonary embolism in a 9-year-old girl: a case report.

Chondrosarcoma is a malignant bone tumour common in adults, third to myeloma and osteosarcoma, but is exceptionally rare in children. Here we discuss a 9-year-old girl presenting with occlusive right pulmonary artery neoplastic embolus, resulting from a primary right proximal humerus chondrosarcoma. To the best of our knowledge, this the first pediatric and only second overall case reported in the United States of a neoplastic pulmonary embolus resulting from a primary chondrosarcoma.

Unusual cause of aborted sudden cardiac death in a teen athlete: homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene.

Common aetiologies of sudden cardiac death in children include coronary anomalies, channelopathies, and cardiomyopathies. Less frequently, hypercoagulable states cause sudden arrest. We report an unusual case of aborted sudden cardiac death in a teenager, ultimately found to have homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene.

Porcine xenograft aortic root replacement in a three month old with severe truncal insufficiency.

Outcomes for truncus arteriosus repair are impacted significantly by the severity of truncal valve dysfunction. When satisfactory repair of the regurgitant truncal valve is unattainable, replacement is required. Given our experience in children with stentless porcine xenografts in the aortic position and the incidence of early valve failure for aortic homografts in infants, we replaced a severely regurgitant truncal valve with a full-root porcine xenograft in a 3-month-old infant. The initial and early result are encouraging, suggesting that the stentless porcine xenograft may be considered an option in cases where primary repair of the truncal (or aortic) valve is not possible.

Peripheral pulmonary artery stenosis: an unusual case and discussion of genetic associations.

Peripheral pulmonary artery stenosis is a common congenital heart lesion associated with several genetic syndromes. We have reviewed the genetics of the lesion and present an unusual case of peripheral pulmonary stenosis involving a newly reported genetic deletion on chromosome 16. Further studies will be needed to confirm association of this genotype and phenotype.

Osteosarcoma with cardiac metastasis in a 22-year-old man: a case report and review of cardiac tumors.

Primary osteosarcoma accounts for 3% of all childhood cancer. It commonly occurs during the adolescent growth spurt and is more common in boys than girls and in African Americans than white people. The 5-year survival is approximately 79%. Cardiac metastasis of osteosarcoma is exceedingly rare; we present an unusual case in a 22-year-old man with significant intracardiac tumor burden. Additionally, we review the current pediatric cardiac tumor literature.

Off-pump snare technique for congenital left atrial appendage aneurysm.

Left atrial appendage aneurysm is an extremely rare anomaly and as such has been rarely imaged or seen intraoperatively with very little accumulated management experience. The available scant published literature stresses resection on cardiopulmonary bypass as the safest and by far the most commonly applied technique. We suggest a novel alternative imaging-guided management utilising an off-pump tourniquet snare technique under live transoesophageal echocardiography.

Leptin-induced endothelial dysfunction: a target for therapeutic interventions.

Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.

Angiotensin-converting enzyme inhibitor nephrotoxicity in neonates with cardiac disease.

Angiotensin-converting enzyme inhibitors (ACEi) are commonly used for pediatric cardiology patients. However, studies examining their safety for neonates with cardiac disease are scarce. The current study aimed to test the hypothesis that ACEi-mediated nephrotoxicity occurs in neonates and may be underappreciated in this population. A retrospective review of 243 neonates with cardiac disease between 2007 and 2010 was performed. Demographic data, weight, length, captopril and enalapril dosing, serum [K⁺], serum creatinine, and concomitant medications during ACEi therapy were recorded and analyzed. Body surface area (BSA), creatinine clearance (CrCl), and change in [K⁺] were calculated. The age range of neonates at ACEi initiation was 15.9-18.1 days. The inclusion criteria was met by 206 neonates: 168 term (82%) and 38 preterm (18%) newborns. Of these neonates, 42% were female, and all the patients had a BSA smaller than 0.33 m² (a group known to have relative renal insufficiency). The mean dose of enalapril was 0.08 ± 0.007 mg/kg for the preterm neonates and 0.08 ± 0.003 mg/kg for the term neonates. The mean dose of captopril was 0.07 ± 0.009 mg/kg for the preterm neonates and 0.13 ± 0.019 mg/kg for the term neonates. A significant decrease in CrCl occurred for both the preterm (p < 0.01) and term (p < 0.001) neonates while they were receiving ACEi. However, the two groups did not differ significantly (p = 0.183). Nearly 42% of all the patients showed renal risk, with approximately 30% demonstrating renal failure by modified pRIFLE (pediatric risk, injury, failure, loss, and end-stage renal disease) criteria. Despite the lack of significantly different CrCl, the premature neonates were more likely to experience ACEi-related renal failure by pRIFLE (55%) than their term counterparts (23%; p < 0.001). Despite its common use for term neonates with cardiac disease, ACEi should be used cautiously and only when indications are clear. These results also raise the question whether ACEi should be used at all for preterm neonates.

Characteristics and outcomes of heart failure-related intensive care unit admissions in children with cardiomyopathy.

OBJECTIVE: The purpose of this study was to describe patient characteristics and outcomes of heart failure (HF)-related intensive care unit (ICU) hospitalizations in children with cardiomyopathy (CM). METHODS AND RESULTS: A query of the Pediatric Health Information System database, a large administrative and billing database of 43 tertiary children's hospitals, was performed. A total of 17,309 HF-related ICU hospitalizations from 2005 to 2010 of 14,985 children ≤18 years old were analyzed. Of those, 2,058 (12%) hospitalizations for CM-HF in 1,599 (11%) children were identified. Classification into CM subtypes was not possible owing to database limitations. The number of yearly CM-HF hospitalizations significantly increased during the study period (P = .036). Overall mortality was 11%, and cardiac transplantation occurred in 20% of hospitalizations. Mechanical circulatory support (MCS) was used in 261 (13%) of hospitalizations. Renal failure, MCS, respiratory failure, sepsis, and vasoactive medications were associated with mortality on multivariable analysis. Significant comorbidities associated with these hospitalizations included arrhythmias in 42%, renal failure in 13%, cerebrovascular disease in 6%, and hepatic impairment in 5%. CONCLUSIONS: HF-related ICU hospitalizations in children with cardiomyopathy are increasing. These children are at high risk for poor outcomes with an in-hospital mortality of 11%.

Coronary artery anatomy in congenital heart disease.

Expanded surgical options and improved outcomes for children born with structural heart defects have ushered a greater clinical interest in the normal and abnormal development of the coronary circulation. Anatomic variations of the coronary system may impact surgical candidacy or operative technique during neonatal life, while others may impact long-term clinical management and planning for subsequent interventions. This review aims to characterize coronary artery anatomy in symptomatic congenital heart disease, emphasizing the clinical consequence of these variations and anomalies.