Craig Sable

Genetic Basis for Congenital Heart Defects: Current Knowledge A Scientific Statement From the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics

The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.

Best Practices in Managing Transition to Adulthood for Adolescents With Congenital Heart Disease: The Transition Process and Medical and Psychosocial Issues: A Scientific Statement From the American Heart Association

Many children born with complex childhood illnesses that historically caused early death are now surviving into adulthood with the expectation of leading meaningful and productive lives. They will ultimately need to transition their care from pediatric to adult-centered care. Unfortunately, in the absence of structured programs to guide this transition, there is often delayed or inappropriate care, improper timing of the transfer of care, and undue emotional and financial stress on the patients, their families, and the healthcare system. At its worst, and as frequently happens now, patients are lost to appropriate follow-up. In fact, the number of adults with congenital heart disease (CHD) in the United States is rising exponentially and now exceeds 1 000 000.1,–,7 At least half of these patients may have complex CHD. Fewer than 30% of adults with CHD are seen by appropriate specialized providers. Fewer than 15% of these patients, who are seen in specialty adult CHD (ACHD) clinics, have CHD that is classified as severe.8 Thus, adolescents with CHD constitute a growing population of individuals for whom a well-planned and well-executed “transition process” is essential. The goals of a formal transition program are to prepare young adults for transfer of care. It should provide uninterrupted health care that is patient centered, age and developmentally appropriate, flexible, and comprehensive. It should include age-appropriate education about medical conditions and promote skills in communication, decision making, self-care, and self-advocacy.9,–,13 It should foster greater personal and medical independence and a greater sense of control over health, healthcare decisions, and psychosocial environment. The ultimate goal of a transition program is to optimize the quality of life (QOL), life expectancy, and future productivity of young patients.14 We acknowledge that the development of ideal transition programs is a …

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions A Scientific Statement From the American Heart Association

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Echocardiography Screening for Rheumatic Heart Disease in Ugandan Schoolchildren

Background— Historically, sub-Saharan Africa has had the highest prevalence rates of clinically detected rheumatic heart disease (RHD). Echocardiography-based screening improves detection of RHD in endemic regions. The newest screening guidelines (2006 World Health Organization/National Institutes of Health) have been tested across India and the Pacific Islands, but application in sub-Saharan Africa has, thus far, been limited to Mozambique. We used these guidelines to determine RHD prevalence in a large cohort of Ugandan school children, to identify risk factors for occult disease, and to assess the value of laboratory testing. Methods and Results— Auscultation and portable echocardiography were used to screen randomly selected schoolchildren, 5 to 16 years of age, in Kampala, Uganda. Disease likelihood was defined as definite, probable, or possible in accordance with the 2006 National Institutes of Health/World Health Organization guidelines. Ninety-seven percent of eligible students received screening (4869 of 5006). Among them, 130 children (2.7%) had abnormal screening echocardiograms. Of those 130, secondary evaluation showed 72 (55.4%) with possible, probable, or definite RHD; 18 (13.8%) with congenital heart disease; and 40 (30.8%) with no disease. Echocardiography detected 3 times as many cases of RHD as auscultation: 72 (1.5%) versus 23 (0.5%; P<0.001). Children with RHD were older (10.1 versus 9.3 years; P=0.002). Most cases (98%) involved only the mitral valve. Lower socioeconomic groups had more RHD (2.7% versus 1.4%; P=0.036) and more advanced disease (64% versus 26%; P<0.001). Antistreptolysin O titers were elevated in children with definite RHD. Conclusions— This is one of the largest single-country childhood RHD prevalence studies and the first to be conducted in sub-Saharan Africa. Our data support inclusion of echocardiography in screening protocols, even in the most resource-constrained settings, and identify lower socioeconomic groups as most vulnerable. Longitudinal follow-up of children with echocardiographically diagnosed subclinical RHD is needed.

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

An elevated echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation in children and adolescents with sickle cell disease. Background Elevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. Design and Methods A prospective multicenter study of 310 patients aged 3–20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. Results Elevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). Conclusions According to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.

Three-Dimensional Printing of Intracardiac Defects from Three-Dimensional Echocardiographic Images: Feasibility and Relative Accuracy

BACKGROUND With the advent of three-dimensional (3D) printers and high-resolution cardiac imaging, rapid prototype constructions of congenital cardiac defects are now possible. Typically, source images for these models derive from higher resolution, cross-sectional cardiac imaging, such as cardiac magnetic resonance imaging or computed tomography. These imaging methods may involve intravenous contrast, sedation, and ionizing radiation. New echocardiographic transducers and advanced software and hardware have optimized 3D echocardiographic images for this purpose. Thus, the objectives of this study were to confirm the feasibility of creating cardiac models from 3D echocardiographic data and to assess accuracy by comparing 3D model measurements with conventional two-dimensional (2D) echocardiographic measurements of cardiac defects. METHODS Nine patients undergoing 3D echocardiography were identified (eight with ventricular septal defects, one with three periprosthetic aortic valve leaks). Raw echocardiographic image data were exported anonymously and converted to Digital Imaging and Communications in Medicine format. The image data were filtered for noise reduction, imported into segmentation software to create a 3D digital model, and printed. Measurements of the defects from the 3D model were compared with defect measurements from conventional 2D echocardiographic data. Meticulous care was taken to ensure identical measurement planes. RESULTS Long- and short-axis measurements of eight ventricular septal defects and three perivalvar leaks were obtained. Mean ± SD values for the 3D model measurements and conventional 2D echocardiographic measurements were 7.5 ± 6.3 and 7.1 ± 6.2 mm respectively (P = .20), indicating no significant differences between the standard 2D and 3D model measurements. The two groups were highly correlated, with a Pearson correlation coefficient of 0.988. The mean absolute error (2D - 3D) for each measurement was 0.4 ± 0.9 mm, indicating accuracy of the 3D model of <1 mm. CONCLUSIONS Three-dimensional printed models of echocardiographic data are technically feasible and may accurately reflect ventricular septal defect anatomy. Three-dimensional models derived from 3D echocardiographic data sets represent a new tool in procedural planning for children with congenital heart disease.

Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence?

Mitochondrial dysfunction has been associated with long-term toxicities of human immunodeficiency virus (HIV) therapy, particularly with the nucleoside analog reverse transcriptase inhibitors (NRTIs). Lactic acidosis, hepatic steatosis, myopathies, cardiomyopathies, neuropathies, and lipodystrophy are frequently attributed to mitochondrial toxicity. Since mitochondrial toxicity could pose a major threat to the long-term success of HIV therapy, the scientific evidence underlying an association between mitochondrial toxicity and antiretroviral therapies, must be carefully examined. There is some data to support the association between NRTIs and mitochondria dysfunction. In this review, we examine human, animal, and in vitro data implicating mitochondrial dysfunction as the causal mechanism of NRTI-associated toxicity in HIV-infected patients.

Echocardiographic Evaluation of Umbilical Venous Catheter Placement

OBJECTIVE: To compare techniques for guiding and confirming placement of umbilical venous catheters (UVCs) using two-dimensional echocardiography.STUDY DESIGN: Fifty-three newborns admitted to our neonatal intensive care unit who required an UVC or who were transferred within 24 hours of UVC placement at a referring hospital were studied. UVC position was assessed by antero-posterior (AP) chest radiography (CXR), lateral CXR, and oxygenation data. The accuracy of the above techniques was compared to echocardiography with saline contrast injection.RESULTS: Echocardiography revealed that UVCs were located ideally at the right atrial/inferior vena cava junction in only 12 (23%) of 53 patients. Twenty-four (45%) were incorrectly positioned in the left atrium. The sensitivity and specificity of AP CXR in evaluating inappropriate UVC position were 32% and 89%, respectively. Lateral CXR and thoracic level on AP CXR did not predict accurately catheter position. UVC pO2 data were not useful in excluding left atrial placement.CONCLUSION: Current methods to determine insertion length and confirm location of UVCs are not adequate. Echocardiography should be considered to confirm correct placement of UVCs.

Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

BACKGROUND Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low‐income and middle‐income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod‐MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age‐standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age‐standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub‐Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability‐adjusted life‐years due to rheumatic heart disease globally. CONCLUSIONS We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25‐year period. The health‐related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.)

Dose Effects and Comparative Effectiveness of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts

OBJECTIVE To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants. METHODS Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25-30 mg) and ER MAS (10, 20, 25-30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale. RESULTS Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations. CONCLUSIONS Dose level, rather than stimulant class, was strongly related to medication response.