Since 2001, the Pediatric Heart Network has published and presented over 150 manuscripts, 85 abstracts, and 75 posters/presentations. This is a complete listing of all manuscripts, categorized by study.
These articles describe the structure and tasks of the PHN, review existing studies, and describe challenges and opportunities for pediatric research in congenital heart defects and acquired heart disease.
W. Lai, Am Heart J 2011; 161:13-67.
J. Kaltman, Circulation 2010; 121:2766-72.
L. Mahony, Pediatr Cardiol 2006; 27:191-198.
The Collaborative Learning study compared how well babies did after surgery at heart centers where babies were removed from the ventilator early versus at sites where babies were not taken off the ventilators early.
W. T. Mahle, Pediatr Crit Care Med; 2016 Oct;17(10):939-947.
This study compared how well babies did after surgery, for Tetralogy of Fallot or coarctation of the aorta, at research sites where babies were removed from the ventilator early (called early extubation) versus at research sites where babies were not taken off the ventilators early. The clinical practice guideline used at the intervention sites significantly increased the rate of early extubation with no change in the rate of reintubation or postoperative ICU length of stay.
M. J. Wolf, Am Heart J; 2016 Apr;174:129-37.
This paper describes how collaborative learning was used to develop a clinical practice guideline to design a study examining early extubation of babies after heart surgery.
K. E. McHugh, Ann Thorac Surg. 2019 May;107(5):1421-1426.
The purpose of this study is to compare outcomes in newborns with congenital heart disease and ductal-dependent pulmonary blood flow who are treated with either catheter-based ductal artery stent (DAS) implantation or surgical systemic-to pulmonary artery shunt (SPS).
C. J. Petit, Catheterization and cardiovascular interventions. 2024 Sep 23.
Some babies are born with a type of critical congenital heart disease in which there is not enough blood flow to the lungs. These babies need a medical procedure within the first few weeks of life to help increase the blood flow to their lungs. Traditionally, they would have surgery to place a shunt, but a newer option is now available that involves placing a ductal artery stent. This paper describes the design of the Pediatric Heart Network’s COMPASS trial, which is the first randomized clinical trial to compare the two treatment strategies (a surgical shunt to a ductal artery stent) to increase blood flow to the lungs in newborn babies with critical congenital heart disease. Participants will be followed over the first year of life and will be monitored for safety, length of stay in the hospital, and other clinical factors.
The purpose of this study was to figure out safe doses of a medicine called dexmedetomidine for babies having heart surgery.
A. F. Zuppa, Br J Anaesth. 2019 Dec;123(6):839-852.
The objectives of this study were to establish a Z-score database for common echo measurements based on a uniformly defined and racially diverse population of normal children from multiple centers over a wide geographic area and to collect electrocardiograms (ECG) from the same population for future establishment of ECG reference values.
L. Lopez, Circ Cardiovasc Imaging 2017; 10(11):e006979.
Data were collected on 3566 healthy nonobese children ≤18 years of age with normal echocardiograms to produce reference values for echocardiogram measurements based on age, sex, race, ethnicity, height and weight. Body size was found to be the best predictor of the sizes of cardiovascular structures, and age, sex, and race did not have a clinically significant effect on this relationship.
E.V. Saarel, Circ Arrhythm Electrophysiol 2018 Jul;11(7):e005808.
Electrocardiography is a cornerstone in the cardiac evaluation of children. Wide variation in previously published data, much of which was obtained before the digital era, provided a strong motivation to obtain more reliable data on electrocardiogram (ECG) measurements in healthy children from North America. This study found that most ECG measurements varied by sex and race and differed from prior studies done in smaller, more racially and ethnically homogeneous populations. This study provides valuable data that can be used clinically for interpreting pediatric ECGs in the modern era for diagnosis or screening of heart disease in North America, particularly for Long QT syndrome and left ventricular hypertrophy.
P. C. Frommelt, J Am Soc Echocardiogr. 2019 Oct;32(10):1331-1338.e1.
D. Truong, Cardiol Young. 2020 Apr;30(4):456-461.
M. E. Alexander, Pediatric cardiology. 2024 Jun; 45 (5):1055-1063.
Electrocardiograms (ECGs) are a primary screening test of cardiac disease in children. They are often the first test obtained when a child sees a cardiologist, and they are obtained on apparently healthy children when looking for hidden cardiac disease. The normal standards used are a mix of older groups, groups lacking in diversity, and only a minority of those standards reference echocardiograms, which are the gold standard for cardiac anatomy and size. The Pediatric Heart Network Normal Echocardiogram Z-score Project provided a diverse group of 2170 healthy children with both ECGs and echocardiograms. We hypothesized that ECG and echocardiographic measures of left ventricular dimensions are sufficiently correlated to imply a clinically meaningful relationship. While the statistical relationship between ECG size and measured echocardiographic left ventricular size was quite strong, those correlations were weak. The majority of differences between ECGs in healthy children could not be easily explained by the size of the heart, the size of the child or the age, sex and race of the child. Thus, our data support deemphasizing the use of traditional measurement-based ECG markers as standalone indications for further cardiac evaluation in children.
This study was done to survey the health status of patients after Fontan surgery and to better understand how tests performed routinely to evaluate heart function relate to overall health status in patients after Fontan surgery.
P. Anderson, J Am Coll Cardiol 2008; 52:85-98.
The Fontan study was designed to study children born with a single ventricle or heart pumping chamber who underwent a type of surgery called the Fontan procedure Data was collected from 546 children between 6 and 18 years of age about their heart structure and function after surgery, ability to exercise, heart rhythm and certain lab tests. Questions were asked to assess physical, mental, and emotional well being. The study showed that most Fontan survivors had a normal sense of well being. Most had normal ability for the heart to squeeze, but the majority had decreased relaxation of the heart muscle. Ability to exercise was also decreased in most. Children with a single right ventricle (pumping chamber) had decreased function of the heart and its valves compared with children with a single left ventricle. If the Fontan procedure was done at an older age, heart valves did not work as well and children were less likely to have a normal heart rhythm.
L. Sleeper, Am Heart J 2006; 152:427-433.
This article describes how the Fontan study was designed and implemented in the Pediatric Heart Network. The purpose of the study was to determine whether clinical measures of how well the heart is working (such as lab tests, exercise testing, and echocardiogram) compare with health status (quality of life) in patients who have had a Fontan procedure for congenital heart disease. The data will help researchers design future clinical trial.
A. Ostrow, Ann Thorac Surg 2006; 82:695-700.
K. Sundareswaran, Ann Thorac Surg 2006; 82(4):1267-75; discussion 1275-77.
D. de Zélicourt, J Thorac Cardiovasc Surg 2006; 131:785-91.
B. McCrindle, Circulation 2006; 113:1123-1129.
Children with a single ventricle (heart pumping chamber) who have undergone the Fontan procedure are at risk of having poor health because of frequent hospitalizations and surgeries, decreased ability to exercise, and other medical problems. Parents of children in the Fontan study answered questions about their child’s physical activity, behavior, emotions and self-esteem. The results showed that as a group, children who have had the Fontan procedure have more problems with vision, speech, hearing, attention, learning, behavior, anxiety and depression compared to children in the general population. The impact of these other problems was made worse by having a lower family income. Future research is needed to identify ways to diagnose, prevent and treat these problems and to recognize the impact they have on children who have had the Fontan procedure.
B. McCrindle, Arch Dis Child 2007; 92:509-514.
The Pediatric Heart Network studied 147 of the children in the Fontan study to see how physically active they were on a daily basis. The researchers found that these children participated in physical activity far less often than healthy children, even if their exercise tests showed that they are able to exercise. Children who spent less time being physically active believed they were less healthy overall, whereas children who were not able to exercise as well not only believed they were less healthy, but also had lower level of physical function and self-esteem.
A. Atz, Cardiol Young 2007; 17 Suppl 2:44-53.
Children with heterotaxy syndrome have been found to have poorer outcomes compared to children with other complex heart problems, even if those children undergo the same surgeries. Eight percent of children in the Fontan study were found to have heterotaxy syndrome. Those children with heterotaxy were compared to children in the Fontan study without heterotaxy, in regards to their medical and surgical history, heart structure and function, ability to exercise, and health status. The study showed that there were no real differences between the two groups in the children’s sense of physical and psychosocial well-being or ability to exercise.
C. Backer, J Am Coll Cardiol 2008; 52:114-116.
This article describes the results of the Fontan study and how those results may change the way we care for children who will need to have the Fontan procedure.
S. Paridon, J Am Coll Cardiol 2008; 52:99-107.
This study discusses the exercise performance of a large group of children in the Fontan study. Of the 546 children in the study, 411 had exercise testing performed, and most (60%) were not able to exercise to peak levels. Those who were able to reach peak exercise were more likely to be older. Many reported fatigue as a reason for not reaching peak exercise. The wide range of performance was found to be related to the whether the heart is able to increase the amount of blood squeezed out of the pumping chamber (stroke volume). The study also showed that as males go through puberty and gain more muscle, the heart after a Fontan procedure may not be able to keep up with increased demands, making exercise more difficult.
A. Blaufox, J Thorac Cardiovasc Surg 2008; 136:100-107.
Problems with heart rate and rhythm are common after the Fontan procedure. The purpose of this study was to see if daily health status in children enrolled in the Fontan study was affected by heart rate or rhythm disorders. Researchers found that a lower resting heart rate and a higher heart rate during exercise were only weakly associated with better physical health. Therefore, other factors may have more impact on how children function after then Fontan procedure.
I. Williams, Cardiol Young 2009; 15:1-11.
Despite improvements in outcomes after surgery, the functional state varies in children who have had the Fontan procedure. This study developed a scoring system for overall function, looking at how the pumping chamber squeezes, the ability to exercise, physical well-being, and certain lab tests. Lower overall function after surgery was found in children who have a right heart pumping chamber, heart pressures that are higher than normal, lower oxygen levels before surgery, abnormal heart rhythms after surgery, and lower income of their caregiver.
R. Margossian, Am J Cardiol 2009; 104:419-428.
The size and function of a single heart pumping chamber (ventricle) are key elements when managing patients after the Fontan procedure. Children in the Fontan study had echocardiograms and MRIs performed as part of the study. This article describes how closely the measurements compare between different doctors who read the studies.
L. Lambert, Pediatrics 2009; 124:e942-949.
Children ages 10-18 enrolled in the Fontan study and their parents completed forms to assess the child’s health status. Parents’ perceptions of the functional health status of their children after the Fontan procedure were worse than the children’s perceptions of their own well being in several areas.
K. K. Whitehead, J Thorac Cardiovasc Surg. 2009 Jul; 138(1): 96–102.
B. McCrindle, Circulation 2010; 121:34-42.
This study looked at how the well being of children who were in the Fontan study related to the test results from echocardiography, MRI, blood and exercise tests. The results showed that the results of these tests were only weakly associated with health status. This suggests that these tests may not be good markers for functional health status.
M. Cohen, Am Heart J 2010; 160:1092-1098.e1.
P. Anderson, Pediatr Cardiol 2010; 31(8): 1219–1228.
A. Prakash, Am J Cardiol 2010; 106(11):1652-6.
E. Stephenson, J Am Coll Cardiol 2010; 56:890-6.
J. R. Darst, Cardiol Young. 2010 Dec; 20(6): 593–601.
J. Rhodes, J Am Soc Echocardiogr 2011; 24:1213-9.
P. Banka, Am Heart J 2011; 162:125-130.
A. Atz, J Am Coll Cardiol 2011; 57:2437-43.
A. Atz, Congenit Heart Dis 2011; 6:313-321.
R. Williams, Echocardiography 2013; 30:1098-1106.
A. Atz, Cardiol Young 2013; 23(3): 335–343.
R. Williams, Congenit Heart Dis 2013;8(1): 32–39.
P. Madan, Am Heart J. 2013 Aug;166(2):365-372.e1.
B. McCrindle, Cardiol Young 2014; 24(3): 469–477.
A. R. Opotowsky, Am J Physiol Heart Circ Physiol. 2014 Jul 1;307(1):H110-7.
R. Margossian, J Am Soc Echocardiogr 2016 Nov;29(11):1066-1073.
J. Rhodes, Pediatrics 2005; 116(6):1339-1345.
Children with congenital heart disease (CHD) often can’t exercise as well as their peers. Part of this may be due to their heart defect and part may be that they may not be very physically active. A 12-week cardiac rehabilitation program was designed to see if children could improve their ability to exercise safely. Sixteen patients completed the program. Improvements were found in 15 of 16 patients and no patient had any heart problems from the exercise.
J. Rhodes, Pediatrics 2006; 118(3):e586-593.
Previous studies have shown immediate benefits when children with congenital heart disease are enrolled in a cardiac rehabilitation (exercise) program. This study aimed to see if the benefits lasted after the exercise program ended. The results showed, compared with children who did not undergo cardiac rehabilitation after the Fontan procedure, children who did participate had significant improvements in exercise function, behavior, self-esteem and emotional state 6 months after their program ended.
This first follow-up to the Fontan study looked at how children and adolescents with single ventricle heart defects who participated in the Fontan Study were doing after their Fontan Surgery.
A. Atz, Congenit Heart Dis 2015; 10(1):E30-42.
B. McCrindle, Pediatr Cardiol 2014; 35(4):632-640.
K. Uzark, J Pediatr 2016; 170:166-172 Epub 2015 Dec 10.
This is a second follow-up study of an existing cohort of children. In this study we would like to learn how these children and young adults, who are now between the ages of 15 and 25 years, have done since their enrollment in Fontan 1.
A. Atz, J Am Coll Cardiol 2017; 69(22):2735-2744.
L. M. Lambert, Am Heart J. 2020 Jun;224:192-200. doi: 10.1016/j.ahj.2020.03.022.
D. J. Goldberg, Pediatr Cardiol. 2020 Sep 25. doi: 10.1007/s00246-020-02465-1.
In the FUEL study, we investigated whether taking a medication called udenafil for 6 months helps improve heart function in children who had a Fontan operation.
D.J. Goldberg, Am Heart J. 2018 Jul; 201:1-8.
This manuscript describes the design of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. It is a trial comparing udenafil to placebo in children and adolescents with single ventricle heart disease who have undergone the Fontan operation. This study will examine changes in exercise capacity, heart performance, and vascular function. These outcomes are important in understanding whether udenafil may be a beneficial medication to maintain health for a longer period in this population.
D.J. Goldberg, Circulation. 2020 Feb 25;141(8):641-651.
M. V. DiMara, Circulation. 2022 Nov 15;15(11):e013676.
The FUEL Echo study was an analysis of the echocardiograms (ultrasounds of the heart) that were performed as part of the FUEL trial. Before this study, it was not known how udenafil affected heart function in patients with a history of Fontan surgery. Overall, patients who received udenafil had improvement in some of the measurements of heart function and also heart filling. Because of the unique way that the Fontan operation works and the limits of what can be understood by ultrasound, more information will be needed to determine exactly how udenafil improves these measurements.
J. B. Edelson, The American journal of cardiology. 2024 Jan 1; 210:183-187.
The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance in children with Fontan physiology. This study showed that there were no clinically significant differences in heart rate or blood pressure in children who took udenafil, even if they were small, young, or taking other medications. This means that there is no need for additional monitoring in patients who start udenafil and are similar to those enrolled in the FUEL trial.
D. J. Goldberg, Pediatric cardiology. 2023 Dec; 44(8):1691-1701.
Although the FUEL Trial demonstrated improvements in submaximal exercise parameters and an echocardiographic measure of ventricular performance in adolescents who had undergone Fontan palliation for single ventricle heart disease, the primary outcome of oxygen consumption at peak exercise did not demonstrate a statistically significant improvement. Recent studies have suggested that the failure to improve peak exercise might be related to the Fontan circulation itself, a circulation in which there is a physiologic ceiling on central venous pressure that limits the ability to improve peak exercise performance. Given this new information, we performed a re-analysis of the data from the FUEL Trial, specifically focused on the cohort with an abnormal baseline oxygen consumption at peak exercise. In this subgroup, we demonstrated that all exercise parameters, including the primary outcome, improved in response to treatment with udenafil. Further, we found an interaction between baseline exercise cohort and treatment group for the outcome of oxygen consumption at peak exercise. A second trial, framed by this new analysis, would be helpful in confirming the utility of udenafil in this population.
This study was done to see if giving a medication called Enalapril (an ACE inhibitor) would improve a baby's growth and heart function in the first year of life.
D. Hsu, Circulation 2010; 122:333-340.
D. Hsu, Am Heart J 2009; 157:37-45.
Angiotensin-converting enzyme (ACE) inhibitors are medicines that improve heart function in adults with heart failure. Infants with a particular type of congenital heart defect (known as single ventricle) have been shown to have abnormal heart function and poor growth. This study was designed to determine if giving ACE inhibitors to babies with single-ventricles would improve their growth, heart function and development. This article describes the design, the participants and the procedures of this trial.
R. Williams, Congenit Heart Dis 2010; 5:96-103.
Many congenital heart defects are associated with low birth weight and prematurity, but there is little information on birth characteristics of babies with a specific kind of defect, single ventricle physiology. This study compares birth parameters for babies enrolled in the Infant Single Ventricle Trial as compared to the typical US population. Infants with single ventricle had increased rates of preterm birth and low birth weight, and they were more likely to be small for gestational age than the general population.
S. Mital, Circulation 2011; 123:2353-2362.
R. Williams, J Pediatr 2011; 159:1017-22.
N. Pike, Cardiol Young 2013; 23(2): 248–257.
C. Ravishankar, J Pediatr 2013; 162(2): 250–256.e2.
J. Cnota, J Thorac Cardiovasc Surg 2013; 145(5): 1288–1296.
I. Williams, Am Heart J 2013; 165(4):544-550.e1.
A. S. Carey, Circ Cardiovasc Genet. 2013 Oct; 6(5): 444–451.
R. Butts, Pediatr Cardiol 2014; 35(5):879-87.
J. W. Gaynor, J Thorac Cardiovasc Surg. 2014 Dec;148(6):2560-6.
J. Gaynor, Pediatrics 2015; 135(5):816-25.
T. Miller, J Pediatr 2016; 168:220-225.
R. Margossian, J Am Soc Echocardiogr 2017; 130(7):699-707.e1.
V. Zak, Cardiol Young 2017; 27(7):1265-1270.
The Pediatric Heart Network developed the Integrated CARdiac Data and Outcomes (iCARD) Collaborative with the goals of leveraging available data sources to aid in efficiently planning and conducting PHN studies; supporting integration of PHN data with other sources to foster novel research otherwise not possible; and mentoring young investigators in these areas.
S. K. Pasquali, Cardiol Young. 2019 Sep;29(9):1121-1126.
This study evaluated pulse steroid therapy in kawasaki disease (KD). The purpose of this trial was to see if adding steroids (methylprednisone) to the standard treatment would improve coronary artery outcomes.
J. Newburger, N Engl J Med 2007; 356(7):663-675.
Children with Kawasaki Disease (KD) are at risk for developing aneurysms (out-pouchings) and enlargement of the coronary arteries, the arteries which bring blood and oxygen to the heart muscle itself. Medications are used to reduce the risk of damage to the coronary arteries and to decrease inflammation. Yet, some children still develop aneurysms and coronary artery enlargement. This trial tested whether adding another type of medication (a corticosteroid) to the standard treatment of aspirin and immune globulin would decrease the amount of coronary artery dilation. The results did not support the use of a steroid in addition for the routine treatment of children with KD.
J. Newburger, N Engl J Med 2007; 356(26):2748.
L. Minich, Pediatrics 2007; 120(6):e1434-40.
Late diagnosis of Kawasaki Disease (KD) increases the risk that a child might have enlargement or aneurysms (out-pouching) of their coronary arteries. This study tried to see how many children in the KD study had a late diagnosis and what factors contributed to a late diagnosis. Being less than 6 months of age, living a greater distance from the hospital and having fewer symptoms (incomplete KD) increased the likelihood of late diagnosis.
B. McCrindle, Circulation 2007; 116:1-6.
This study looked at how coronary artery size changes during when a child has Kawasaki Disease (KD) by performing echocardiograms at the time of diagnosis, at one week and five weeks after diagnosis. The results showed that, in most patients, the coronary arteries are most dilated at the time of diagnosis of KD and they decrease in size over time. The KD study also showed that aneurysms (bulges or outpouches) in the coronary arteries were infrequent.
A. Baker, J Pediatr 2009; 154(4):592-595.
Many children with Kawasaki disease (KD) have other symptoms that may lead to a delay in the diagnosis of KD. This study investigated common symptoms in children in the KD study (in addition to the symptoms of KD) in the 10 days before they were diagnosed with KD. Symptoms reported were irritability, vomiting, decrease in food/fluid intake, coughing, diarrhea, runny nose, weakness, stomach pain, and joint pain. Symptoms of KD can often be accompanied by symptoms commonly found in other common childhood illnesses. Clinicians should consider the diagnosis of KD, even when other common symptoms are present.
B. Printz, J Am Coll Cardiol 2011; 57:86-92.
L. Sleeper, J Pediatr 2011; 158:831-5.
R. Margossian, J Am Soc Echocardiogr 2011; 24(1):53-9.
This study was done to compare two drugs (Atenolol and Losartan) to see if one is better than the other at slowing the speed of aortic enlargement. The study also compared the kinds of side effects that can occur when taking either of these medicines.
R. Lacro, N Engl J Med 2014; 371:2061-2071.
Among 608 children and young adults with Marfan’s syndrome (ages 6 months to 26 years) who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. Aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.
R. Lacro, Am Heart J 2007; 154:624-631.
The leading cause of death in people with Marfan syndrome is dilation, tearing and rupture of the aorta, the large artery that delivers blood from the heart to the body. Recent studies in mice with Marfan syndrome showed that treatment with Losartan, a medication used to treat high blood pressure, prevented dilation and improved the structure of the wall of the aorta. This article describes the design of a trial to compare Losartan to the standard medication (Atenolol) for patients with Marfan syndrome. The goal of the trial is to follow over 600 children and young adults for 3 years to determine which drug does a better job slowing the rate of growth of the aorta.
E. Selamet Tierney, J Am Soc Echocardiogr 2013; 26(6):657-666.
This study describes the characteristics of the echocardiograms for subjects enrolled in the clinical trial. Even when different doctors reviewed and measured the aortas and heart structures of the trial participants, there was excellent agreement in the measurements. Having good agreement is important for accurately reporting the results of the clinical trial.
R. Lacro, Am Heart J 2013; 165:828-835.e3.
This paper describes the population that was screened and then enrolled in the clinical trial. The average age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. Aortic root diameter z-score was 4.0 and wasn’t different by age. Mitral valve prolapse and mitral regurgitation were more common in females. 56% had a family member with aortic surgery and 32% had a family member with a history of aortic dissection.
ES. Selamet Tierney, Am J Cardiol 2018 May 1;121(9):1094-1101.
The PHN randomized trial of atenolol versus losartan in Marfan Syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. This analysis examined treatment effects on aortic stiffness and determined whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. There was no treatment effect on the rate of change for ascending-aorta stiffness index, aortic-root elastic modulus, or ascending-aorta elastic modulus. We found that atenolol therapy was associated with a fall in aortic-root stiffness index, while losartan therapy was not. Higher baseline aortic-root stiffness index and elastic modulus were associated with a smaller decrease in aortic root z-score and increased risk for clinical outcomes. These data suggest that non-invasive aortic stiffness measures may identify patients at higher risk for progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy for such patients.
A. Hoskoppal, Pediatr Cardiol 2018 Jun 11. doi: 10.1007/s00246-018-1916-6.
This was a secondary analysis of the PHN randomized clinical trial of atenolol vs. losartan in patients with Marfan syndrome that attempted to identify factors that predict rapid aortic root dilation and referral for aortic surgery. We found some statistically significant but only weakly predictive associations between more rapid aortic root dilation and older age, non-white race, and one aortic measurement: higher sinotubular junction z-score. We found similarly statistically significant but only weakly predictive associations between referral for aortic root surgery and some aortic measurements (larger aortic root diameter, higher ascending aorta z-score, and higher ratio between the diameters of the sinotubular junction and ascending aorta). Future studies may clarify whether monitoring generalized proximal aortic dilation and effacement of the sinotubular junction will help to risk-stratify young patients with Marfan syndrome and inform medical and surgical management.
D. Y. Mah, Am J Cardiol. 2018 Jul 17. pii: S0002-9149(18)31424-3. doi: 10.1016/j.amjcard.2018.07.006.
J. C. Handisides, J Pediatr. 2019 Jan;204:250-255.e1. doi: 10.1016/j.jpeds.2018.08.061.
S. Driest, J Pediatr. 2020 Jul;222:213-220.e5. doi: 10.1016/j.jpeds.2020.03.064.
M. S. Hamstra, Clin Trials 2020 Aug 21;1740774520945988. doi: 10.1177/1740774520945988.
J. A. N. Meester, Genetics in Medicine 2022 Jan. doi: 10.1016/j.gim.2021.12.015.
The purpose of our study was first to identify how many people with Marfan syndrome in the study have a mutation in the FBN1 gene. Afterwards, we investigated if the type of FBN1 mutation is associated with specific symptoms and whether the type of mutation made the treatment work any better or worse. In total, 373 young patients with Marfan syndrome participated in our study. We identified an FBN1 mutation in 91% of participants in our study. A dislocated eye lens happened more often in participants with dominant-negative gene mutations (which are mutations that lead to an abnormal protein) than in those with haplo-insufficient mutations (which are mutations that lead to lower levels of normal protein). In participants with a dominant negative mutation, a dislocation of the eye lens happened more often if the mutation was located at the beginning of the protein (84%) than if the mutation was found towards the end of the protein (17%). If a dominant negative mutation was present in the middle of the protein, the participants had more severe cardiovascular symptoms. We could not prove whether the type of mutation made treatment work any better. In conclusion, we described new links between the type of gene mutation and symptoms in Marfan syndrome. Our findings will provide more information for families with Marfan syndrome about their condition.
A. Pitcher, Lancet 2022 Aug. doi: 10.1016/S0140-6736(22)01534-3.
People with Marfan syndrome may have enlargement of the aortic root, and medications are often used to try to slow the rate of enlargement. This study combined data from 7 trials and 1442 patients with Marfan syndrome to see whether two types of medications (angiotensin receptor blockers and β blockers) could slow the rate of enlargement of the aortic root. The study found that, in people with Marfan syndrome and no previous aortic surgery, angiotensin receptor blockers reduced the rate of increase of the aortic root by about one half, even among those who were already taking a β blocker. The effects of β blockers were similar to those of angiotensin receptor blockers. They concluded that a combination of a β blocker and an angiotensin receptor blocker could reduce the rate of enlargement of the aortic root by at least one half, and potentially by much more than this, which may delay the need for aortic surgery.
This study looked at how adults with congenital heart disease (CHD) learn and think about the world around them.
S. Cohen, American Heart Journal. 2023 Aug; 262:131-139.
Children with congenital heart disease (CHD) often have a hard time thinking, remembering, or paying attention. But we don’t know if adults with CHD have the same trouble, and we don’t know how CHD reacts with other heart problems that happen when you are an adult to affect the brain. This paper describes a study called, the Multi-Institutional Neurocognitive Discovery Study in Adult Congenital Heart Disease (MINDS-ACHD). The purpose of MINDS-ACHD was to see how common it is for adults living with CHD to have difficulty with brain function. This paper describes how MINDS-ACHD was designed and run at different hospitals in the United States and Canada. The results of MINDS-ACHD will help doctors diagnose and treat adults living with CHD who have concerns about their brain function.
A. Panigrahy, J Cardiovasc Dev Dis. 2023 Sep 6; 10(9):381.
Babies born with heart disease are much more likely to live than previously. In the 1960’s, less than 10% lived into adulthood, but now over 90% do. Therefore, there are many more adults living with congenital heart disease than there used to be, and it’s important to study problems they have with attaining an education, holding jobs, and having a social life. While the MINDS Study evaluates these, we describe a sub study looking at brain images with the goal of understanding how brain injuries caused by heart disease are associated with mental abilities. Results from this research will help shape the medical care of adults living with heart conditions with which they were born..
This was a study of ACE inhibition therapy in children with mitral regurgitation (MR) after Repair of an Atrioventricular Septal Defect (AVSD).
L. Minich, Ann Thorac Surg 2010; 89:530-536.
There have been many improvements in the surgery and care of children with atrioventricular septal defects (AVSD. This article describes the outcomes at 1 and 6 months after repair for children with two particular types of AVSD: partial and transitional AVSDs. Children had short hospital stays and few adverse events around the time of surgery. Also, children who were growing poorly before surgery showed good catch-up growth if the surgery was performed between 3 and 18 months of age. Some children have leaking of the left-sided atrioventricular valve after surgery, particularly if surgery is performed after age four.
J. Li, Am Heart J 2011; 161:233-40.
The Pediatric Heart Network designed a placebo-controlled randomized trial to test the effect of enalapril on the amount of left heart valve regurgitation after atrioventricular septal defect (AVSD) repair. Prior to the launch of the trial, a feasibility study was performed to estimate the number of patients with at least moderate mitral regurgitation following AVSD repair. The study was subsequently terminated due to low patient accrual. Several factors led to the problems with enrolling patients: 1) the feasibility study used chart review to assess for valve regurgitation but the trial used echocardiography measurements; 2) clinicians and referring physicians were already believing that enalapril was a good drug to give and many patients eligible for the study were already taking the drug; 3) the echocardiography methods used were developed in adult populations and not children; 4) there are no good data to define the natural history of the disease process.
A. Atz, J Thorac Cardiovasc Surg 2011; 141:1371-9.
This study evaluated contemporary results after repair of a complete atrioventricular septal defect (AVSD) and to determine factors associated with poorer outcomes. Particular attention was paid to type of surgical repair, age at surgery, and presence of Trisomy 21. The type of surgical repair and having Trisomy 21 did not increase the risk of death or serious medical problems. Mortality and morbidity were low. Age at repair ≤2.5 months and need for concurrent surgical procedures were not associated with residual defects or degree of heart valve regurgitation, but were associated with higher resource utilization.
A. Kaza, Ann Thorac Surg 2011;92:1468-75.
Atrioventricular septal defects (AVSD) include abnormalities involving the walls between the heart chambers (atrial and ventricular septa) and the heart valves. The investigators compared patient characteristics, resource utilization, center differences, and outcomes among different types of AVSD. Survival in the current era is excellent, with few residual defects after surgical repair for all AVSD subtypes. Repair of the valves failed to decrease moderate or severe valve regurgitation at the 6-month follow-up. Being older when the heart is repaired increases the risk of moderate or severe valve regurgitation.
A. Prakash, Pediatr Cardiol 2012; 33:205-214.
It is difficult to quantify the amount of regurgitation from the mitral valve using echocardiography. Since children who have an atrioventricular septal defect repaired continue to have varying amounts of mitral regurgitation, the accuracy of proposed echocardiographic methods was proposed to evaluate the severity of the regurgitation. No method performed well. No method proved to be better than the echocardiographer’s subjective assessment of the size of the color Doppler jet and surrounding structures. Reliable assessment of mitral regurgitation remains challenging in this population.
MIS-C is a new condition related to COVID-19, so we are still learning about its causes and effects. This study will help us learn more about MIS-C and its effects on long-term health of children.
D. T. Truong, American Heart Journal. 2022 Jan; 243:43-53.
Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, but serious, complication of COVID-19 in people who are younger than 21 years-old. The illness causes inflammation and injury to various organs, including the heart. The “Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC)” study was developed to better understand the recovery of the heart and other organ systems in children, adolescents, and young adults with MIS-C. The publication “The NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives” describes reasoning and the methods for the MUSIC study. The goals of the study include understanding the timing of recovery of the squeeze of the heart and of enlargement of the coronary arteries (small blood vessels that bring oxygen to the heart). Other goals of the study are to describe how MIS-C affects other organs and their recovery over time, as well as monitor for development of new symptoms over time. The study plans to enroll at least 600 participants across 33 North American pediatric hospitals. The study will collect data from participants’ hospitalization and follow the participants for up to 5 years using a yearly medical questionnaire about general health, the heart, and all the organ systems.
M. D. Elias, JAMA Network Open. 2023 Jan 3;6(1):e2248987.
The multisystem inflammatory syndrome in children (MIS-C) is a complication of COVID-19, and it can cause heart issues among children. The COVID-19 vaccine can prevent children from being very sick with COVID. Some families and providers worry about the risks of the vaccine after MIS-C. This study evaluated reactions to the vaccine after MIS-C. There were no serious complications reported among 185 children. Many reported minor side effects (fatigue, arm soreness) similar to the general public.
The purpose of this study was to see if a program of gentle physical exercise is safe and helps babies to grow after having surgery to repair their hearts.
L.M. Lambert, Cardiol Young 2017; 27(7):1361-1368.
This non-randomized pilot study enrolled 20 neonates after surgery for heart repair. The aim was to evaluate the safety and feasibility of a passive range of motion exercise program, administered by trained physical therapists for up to 21 days or until hospital discharge. We found the exercise program to be safe for babies with complex congenital heart disease after surgery and feasible to perform.
The PHN Scholar Program is a career development program to train the next generation of clinician-scientists in pediatric cardiology-related research, a historically underfunded area. The program awards study grants to support outstanding researchers in the field of translational, clinical, health services, or epidemiological pediatric cardiovascular disease or adult congenital heart disease.
L.L. Minich, Cardiol Young 2018 Jun;28(6):854-861.
The Pediatric Heart Network designed a career development award to train the next generation of clinician-scientists in pediatric cardiology-related research, a historically underfunded area. This manuscript described strengths and weaknesses of the program and the scholars’ academic achievements for the first two funding cycles. Strengths included clarity and fairness of the review, but feedback on the application was not considered useful. The highest rated benefits were expanding the scholar’s collaborative network and increasing publication potential. The 13 scholars were first/senior authors for 97 abstracts and 109 manuscripts, served on 22 PHN committees, and were awarded $9,673,660 in subsequent extramural funding for a return of ~$10 for every Scholar dollar spent.
The aim of this research was to study whether a scoring system called the Residual Lesion Score could predict how children with congenital heart disease do after cardiac surgery.
M. Nathan, Ann Thorac Surg 2016 Oct 7. pii: S0003-4975(16)30916-X.
The purpose of this study was to assess the accuracy of heart surgery data obtained from a registry compared with data copied from babies’ medical charts by research coordinators. Most PHN sites participate in a registry called “the Society of Thoracic Surgeons- Congenital Heart Surgery Database” in which each site collects data around the time of surgeries. For a select set of variables (like blood pressure, length of hospital stay etc), we found that 94.7% of data elements were both complete and accurate within the registry, suggesting that registry data can be an efficient source for research studies.
M. Nathan, J Thorac Cardiovasc Surg 2019 Nov 15. pii: S0022-5223(19)32761-8.
Outcomes after surgery for congenital heart disease may be impacted by a wide variety of variables. Risk for adverse outcomes begins before surgery and includes innate characteristics such as birth weight, gestational age, genetic abnormalities, and complexity of congenital heart disease (CHD), as well as factors such as hemodynamic stability, adequacy of diagnostic evaluation, prior cardiac operation(s), and appropriateness of surgical plan. Intraoperative risk factors relate to cardiopulmonary bypass, surgical technique, adequacy of intraoperative imaging, subsequent decision to return (or not) to bypass for residual lesions identified, and early post-bypass hemodynamic management. The postoperative milieu may also contribute to outcomes, particularly through serious medical events and complications. The presence of residual lesions (intended or unintended postoperative structural cardiac abnormalities, including those persisting from the preoperative state or newly acquired consequent to the surgical procedure) may be among the most important factors in determining long-term clinical outcomes and costs. The “Residual Lesion Score” (RLS) is a novel tool for evaluating the status of repair across operations and centers. The prospective multi-center RLS study, funded by the National Heart Lung and Blood Institute’s Pediatric Heart Network (PHN), seeks to validate the association of the RLS with early and mid-term postoperative outcomes for common congenital cardiac operations in a multicenter environment. The RLS can serve as an instrument for quality improvement and support future research on perioperative strategies to improve outcomes of congenital heart surgery.
C. J. Prospero, Cardiol Young. 2019 Jul;29(7):930-938.
B. R. Anderson, Cardiol Young. 2020 Jun;30(6):807-817.
J. C. Levine, Cardiol Young 2024 Mar: 34(3)570-575.
This was a descriptive paper outlining our challenges and solutions and was designed to help others who may wish to carry out similar projects. This study reviewed some of the unique considerations related to planning and executing the review of echocardiographic images in the Residual Lesion Score study when the participants are in the infant age range. These unique considerations included those related to imaging of patients who may not be able to cooperate with data acquisition, imaging of patients with complex anatomic variants and coordinating uniform data collection across a large number of centers with variable imaging requirements and styles. Finally, we reviewed the lack of technical infrastructure that currently exists to support this type of data review and the efforts that we went through to modify existing platforms and create some unique software.
M. Nathan, Cardiol Young 2022 Dec 23: 1-14.
The Pediatric Heart Network conducted a study to test a new tool called the Residual Lesion Score. This tool helps doctors assess if there are any remaining heart defects after surgery for congenital heart defects. It uses ultrasound images called echocardiograms and also considers if any unexpected additional procedures were needed after the initial heart surgery before the child leaves the hospital.
The Residual Lesion Score was developed based on a previous tool called the Technical Performance Score. Experts used the RAND Delphi methodology to refine the Technical Performance Score to develop the Residual Lesion Score. This method involves rating the quality of different measures on a nine-point scale, where higher numbers indicate better quality. The scale helps ensure that the ratings are fair and not influenced by dominant voices in the group.
A panel of 11 experts in pediatric heart care, under the guidance of experts, reviewed and provided feedback on the Residual Lesion Score. They looked at its validity (how well does it measures what it is supposed to) and feasibility (how practical is it to use) for five common heart surgeries in infants. These surgeries include:
1. Repair of tetralogy of Fallot with pulmonary stenosis
2. Repair of complete atrioventricular septal defect
3. Arterial switch operation for dextro-transposition of the great arteries
4. Repair of coarctation of the aorta or related conditions
5. Norwood procedure for single ventricle anatomy
The experts first reviewed the tool via email and then met in person to discuss and refine it. Based on analysis of the final validity and feasibility scores from experts, we developed the final Residual Lesion Score for each of these surgeries. These scores were then tested in the Pediatric Heart Network’s Residual Lesion Score study.
The purpose of this study was to find out whether the medicine called apixaban (commonly known as Eliquis®) is safe for children with heart disease, and to learn how much apixaban will be present in the blood after taking a certain dose.
R. M. Payne, Am Heart J. 2019 Nov;217:52-63.
R. M. Payne, JACC. 2023 Dec, 82 (24)2296-2309.
Children with heart disease sometimes need blood thinners to avoid strokes or other heart problems. Until now, the only blood thinners we had to use were warfarin and an injectable form of heparin, which we also use in adults for the same purpose. However, children are hard to treat with these drugs because they are so active, putting them at risk of bleeding, and because their diet may change, and this can change the level of blood thinner needed to keep them safe. In addition, we need to draw frequent blood samples in children to measure the blood thinner level and adjust the dosage. To get around these problems, we conducted an extensive worldwide trial of a new blood thinner called apixaban in children with heart disease. This blood thinner has already been approved for use in adults but has not been formally tested for use in children. This trial showed that apixaban was safe, well-tolerated for children, and as effective as the standard of care, warfarin, and heparin. No child had a stroke or cardiac problem during the trial. Additionally, apixaban does not require blood level monitoring and does not react or change depending on the child’s diet. This clinical trial also established the appropriate dose for children of different weights. This trial has helped to advance our care and treatment of children with heart disease and has made it safer to provide blood thinners for them.
The Single Ventricle Reconstruction (SVR) Trial was done to evaluate two commonly placed shunts to see which one would improve how patients do following the Norwood procedure.
R. Ohye, N Engl J Med 2010; 362(21):1980-1992.
In children with a single heart ventricle undergoing the Norwood procedure, a trial was conducted to determine if one of two different shunts resulted in better survival after 12 months without the need for a heart transplant. Babies were randomly assigned to receive either the traditional modified Blalock-Taussig shunt (MBTS) or the right ventricle- pulmonary artery (RV-PA) conduit. The study showed that babies who received the RV-PA conduit had better survival without needing a heart transplant 12 months after entering the study. However, when the babies were followed for a longer period of time, there was no difference between the two groups. The results also revealed that babies who received the RV-PA conduit needed more procedures and had more complications than those receiving the MBTS.
R. Ohye, J Thorac Cardiovasc Surg 2008; 136:968-975.
The first of the three surgeries (the Norwood procedure) for babies born with a single heart ventricle is one of the highest risk procedures in congenital heart surgery. Two types of shunts (tubes) may be used for the first surgery: the traditional modified Blalock-Taussig shunt (MBTS) and the right ventricle to pulmonary artery (RV-PA) shunt. Some research has shown one technique to be better than the other, but other research has shown no differences in the outcomes for each technique. This article describes a trial designed by the Pediatric Heart Network to compare the two types of shunts. In the study, babies were randomly assigned to receive either the MBTS or the RV-PA shunt, and they were followed over time to compare the outcomes.
R. Ohye, Pediatr Cardiol 2007; 28:122-125.
Babies born with a single heart ventricle require multiple surgeries in order to provide adequate blood flow to the body. The first of the three surgeries is one of the highest risk procedures in congenital heart surgery. Two types of shunts (tubes) may be used for the first surgery: the traditional modified Blalock-Taussig shunt (MBTS) and the right ventricle to pulmonary artery (RV-PA) shunt. This article explains the advantages and disadvantages of each shunt and the Pediatric Heart Network’s clinical trial to determine if one shunt type is better than another in this population (see results of the PHN trial).
A. Atz, J Thorac Cardiovasc Surg 2010; 140:1245-1250.
J. Johnson, Pediatr Cardiol 2011; 32:479-486.
L. Virzi, J Thorac Cardiovasc Surg 2011; 142(3): 531-537.
J. Newburger, Circulation 2012; 125:2081-2091.
J. Tweddell, J Thorac Cardiovasc Surg 2012; 144(1):152-159.e2.
P. Frommelt, Circulation 2012; 125:2630-2638.
S. Pasquali, J Thorac Cardiovasc Surg 2012; 144:915-21.
S. Tabbutt, J Thorac Cardiovasc Surg 2012; 144:882-95.
N. Ghanayem, J Thorac Cardiovasc Surg 2012; 144:896-906.
R. Ohye, J Thorac Cardiovasc Surg 2012; 144:907-14.
E. Bacha, J Thorac Cardiovasc Surg 2012; 144(4): 880-1.
W. Mahle, Pediatr Cardiol 2013; 34(2):327-333.
P. Frommelt, J Am Soc Echocardiogr 2013; 26:521-9.
K. Hill, Circulation 2013; 128(9): 10.1161/CIRCULATIONAHA.112.000488.
G. Marx, Circ Cardiovasc Imaging 2013; 6(6): 934–942.
S. Schwartz, J Thorac Cardiovasc Surg 2014; 147(6):1791-8, 1798.e1-4.
L. Lambert, J Pediatr 2014; 164(2): 237–242.e1.
M. Nathan, J Thorac Cardiovasc Surg. 2014 Nov;148(5):2208-13, 2214.e1-6.
R. Aiyagari, J Thorac Cardiovasc Surg 2014; 148(4):1467-74
J. Johnson, Am J Cardiol 2015; 116(8):1263-9.
G. D. Hill, J Am Soc Echocardiogr. 2015 May; 28(5): 517–521.
S. Bradley, J Thorac Cardiovasc Surg 2016; 152(1):195-6.
D. Mah, J Thorac Cardiovasc Surg 2016; 152(1):189-94.
J. Elhoff, Pediatr. Crit. Care Med 2016; 17(1):30-5.
M. Oster, J Am Heart Assoc 2016; 13;5(1). pii: e002566.
International Cardiac Collaborative on Neurodevelopmental (ICCON) Investigators. Ann Thorac Surg. 2016; 102(3):843-849.
A. Kulkarni. J Heart Lung Transplant. 2016 Mar;35(3):306-311.
K. E. McHugh. Cardiol Young. 2016 Oct;26(7):1303-9.
R. Ramroop, J Thorac Cardiovasc Surg. 2017; 154(5):1703-1710.e3.
M.E. Oster, J Thorac Cardiovasc Surg 2017 Mar;153(3):638-645.e2.
T. Karamlou, J Thorac Cardiovasc Surg 2017 Dec;154(6): 2038-2040.
P. Gupta, J Thorac Cardiovasc Surg 2017 Dec;154(6):2030-2037.e2.
J. M. Meza, Circulation. 2017 Oct 31; 136(18): 1737–1748.
K. E. McHugh, Ann Thorac Surg. 2018 Mar; 105(3): 851–856.
E. Jean-St-Michel, Pediatr Cardiol 2018 Jun;39(5):955-966.
M.S. Cohen, J Am Soc Echocardiogr. 2018 Jul 3. pii: S0894-7317(18)30249-9.
We assessed whether left ventricular size and function influence right ventricular function and clinical outcomes after staged palliation for single right ventricle anomalies. In the Single Ventricle Reconstruction (SVR) trial cohort, we studied left ventricle size and function compared to echocardiography-derived measures of right ventricular size and function as well as tricuspid regurgitation. We also assessed the impact of the left ventricle on outcome (death and/or heart transplantation). The hypoplastic left heart syndrome subtype of aortic atresia/mitral atresia was less likely to have a measurable left ventricle compared to other subtypes. Right ventricle end-diastolic and end-systolic volumes were significantly larger, while diastolic indices suggested better properties in those subjects with no measurable left ventricle compared to those with measurable ventricles. Right ventricular ejection fraction and tricuspid regurgitation were not different based on left ventricle size and function. There was no difference between groups in transplantation-free survival up to 14 months of age. In patients with single right ventricle anomalies, left ventricular size and function has a minimal short-term impact on survival and right ventricular performance.
K. R. Wolfe, Pediatr Pulmonol. 2019 Jun;54(6):922-927.
J. Bainton, Cardiology in the Young. 2023 Jan 5; 1-10.
Post-traumatic stress disorder occurs in parents of infants with CHD, contributing to psychological distress with detrimental effects on family functioning and well-being. We sought to determine the prevalence and factors associated with post-traumatic stress disorder symptoms in parents whose infants underwent staged palliation for single ventricle heart disease. The study population included 215 mothers and fathers who were assessed for symptoms of post-traumatic stress disorder at three timepoints, including post Norwood, post-Stage II, and a final study timepoint when the child reached approximately 16 months of age, using the self-report questionnaire Impact of Event Scale – Revised. The prevalence of probable post-traumatic stress disorder post-Norwood surgery was 50% of mothers and 39% of fathers, decreasing to 27% of mothers and 24% of fathers by final follow-up. Intrusive symptoms such as flashbacks and nightmares and hyperarousal symptoms such as poor concentration, irritability, and sudden physical symptoms of racing heart and difficulty breathing were particularly elevated in parents. Higher levels of anxiety, reduced coping, and decreased satisfaction with parenting were significantly associated with symptoms of post-traumatic stress disorder in parents. Demographic and clinical variables such as parent education, pre-natal diagnosis, medical complications, and length of hospital stay(s) were not significantly associated with symptoms of post-traumatic stress disorder. Parents whose infants underwent staged palliation for single ventricle heart disease often reported symptoms of post-traumatic stress disorder. Symptoms persisted over time and routine screening might help identify parents at-risk and prompt referral to appropriate supports.
In this first follow-up to the SVR Trial, we wanted to learn if these same children (2-6 years of age) do better with one of the two shunts (RV-to-PA or MBTS) in the years after surgery. We also explored how other medical and surgical factors affect children's health and how they develop.
J. Newburger, Circulation 2014; 129:2013-2020.
In the Single Ventricle Reconstruction (SVR) trial, 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups. By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with better transplant-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions.
C. Goldberg, J Pediatr 2014; 165(3): 490-496.
This study measured neurodevelopment at 3 years of age and compared it to neurodevelopment at 14 months of age in children enrolled in the Single Ventricle Reconstruction trial. Scores on tests to evaluate neurodevelopment were lower at 3 years of age when compared to a normal population. The results suggest that even when 14-month scores are within the normal range, children with single ventricle heart defects may be at risk for developmental impairment at pre-school age and beyond. Therefore, all children with HLHS and related single ventricle malformations should be followed longitudinally to improve recognition of delays and potential for intervention.
P. Burch, J Am Heart Assoc 2014; 3(3):e000079.
Poor growth is associated with poor prognosis in several disease processes. While children with single ventricle heart disease are known to be smaller than their peers at birth, there is limited information regarding growth and development in survivors. In this paper we show that single ventricle survivors continue to grow poorly with regards to both height and weight through the first two surgical palliations and at three years of age.
P. Frommelt, J Am Coll Cardiol 2014; 64(19):2026-35.
The initial shunt type at the Norwood procedure used to supply blood flow to the lungs in infants with single right ventricle anomalies may influence heart muscle function during the second and third years of life. This study tested heart muscle function in children in the SVR trial, comparing those who had a right ventricle-to-pulmonary artery shunt versus the modified Blalock-Taussig shunt. While there were no differences between the groups, a markedly enlarged heart, poor heart muscle function, and significant heart valve enlargement/dysfunction at 14 months of age was associated with poorer survival to the Fontan operation.
C. Ravishankar, J Thorac Cardiovasc Surg. 2016; 151(3):669-675.
In the Single Ventricle Reconstruction trial, infants with hypoplastic left heart syndrome (HLHS) who received a right-ventricle-to-pulmonary-artery shunt (RVPAS) versus a modified Blalock-Taussig shunt (MBTS) had lower early postoperative mortality, but more complications at 14 months. This study explored the effect of shunt type and other patient, medical, and surgical factors on postoperative length of stay (LOS) after the Fontan operation. The type of shunt received at the Norwood surgery did not affect how long a baby stayed in the hospital for the Fontan surgery. Rather, more medical complications before the operation resulted in longer LOS after the Fontan operation.
A. W. Eckhauser, Cardiol Young. 2019 Dec;29(12):1510-1516.
N. Cain, Journal of the American College of Cardiology 2022; 169:107-112.
This study compared the effect of both shunt type and Fontan type on the incidence of abnormal heart rhythms (arrhythmias) by 6 years of age in the Pediatric Heart Network Single Ventricle Reconstruction Extension Study (SVRII). By 6 years of age, benign ventricular beats were common in the SVR II population, and it was common for participants to be on medication to treat abnormal heart rhythms, but most of those medications also support heart function. Of the 7 patients with death or transplant between 2-6 years, none had ventricular arrhythmias, but compared with transplant-free survivors, they had some differences in ECG measurements (a longer QRS and a trend toward a longer QTc interval). Fast arrhythmias that begin in the top chambers of the heart (atrial tachyarrhythmias) varied by Fontan type, but not by shunt type. We concluded that, despite the potential for increased risk of ventricular arrhythmias and sudden death in the RV to PA shunt group, the data from the SVR and SVRII studies do not show any significant differences by shunt type or increased risk by 6 years of follow-up. The findings support the need for ongoing surveillance for arrhythmias in the SVR population.
K. A. Mussatto, The Journal of Pediatrics 2023; 255:50-57.
Hypoplastic left heart syndrome (HLHS) has a significant impact on both children and families. The purpose of this study was to gain an understanding of how family factors (parent mental health, quality of life, family resources, function and family management of condition) are associated with psychosocial outcomes in children with HLHS at 6 years of age. Parent mental health, quality of life, family resources and family function had no significant relationships to child psychosocial outcomes. Parent perceptions that their child had a normal life despite their heart condition, that the condition was manageable and had a lower impact on family daily life were associated with better child adaptive behavior, adaptive skills and fewer internalizing behavior problems (depression, anxiety, somatic complaints). Improved understanding of the associations between family factors and child outcomes should guide counseling and the development of tailored interventions to capitalize on each family’s strengths.
This is a second follow-up of the Single Ventricle Reconstruction (SVR) trial which aimed to see which shunt type was best for infants with single ventricle heart defects undergoing the Norwood operation. The purpose of this study is to see which type of shunt is most effective by later school age.
P. Burch, J. Pediatr. 2017; 180:270-274.e6.
There is limited information regarding the long-term growth and development in survivors with single ventricle heart disease. This paper assesses growth in these patients after their final palliative surgery until they are school age. These children continue to grow poorly with regards to both height and weight with height being affected to a greater extent than weight.
W.T. Mahle, J Heart Lung Transplant. 2018 Jul;37(7):879-885.
Heart failure is a known complication following the Norwood procedure for single ventricle anomalies. Examination of the Single Ventricle Reconstruction (SVR) trial cohort revealed that almost 15% of participants developed heart failure following discharge from the Norwood procedure. Shunt type had no association with heart failure. The risk for developing heart failure was highest in the first year of life. Over half of the children who developed heart failure were listed for transplant, though a significant number died while awaiting a transplant. Among transplant-free survivors to 6 years of age, fewer than 5% of children with palliated single ventricle congenital heart disease had class IV symptomatic heart failure. Several procedure and patient-related factors were associated with development of heart failure, including impaired right ventricular function after the Norwood procedure.
K. Mussatto, Cardiol Young. 2018; 28(1):126-133.
Children with hypoplastic left heart syndrome are at a risk for neurodevelopmental delays. This study looked at the types of early intervention services (e.g. speech, occupational, physical therapy) and how frequently services were used from age 1 to 4 years in children who participated in the SVR trial. Significant delay was reported by parents in 18-43% of children at ages 3 and 4. More than half of the children (52-69%) were not receiving services at any age and 20-32% were receiving two or more therapies each year. Despite significant neurodevelopmental delays, early intervention service utilization was low in this group of children.
J.W. Newburger, Circulation. 2018 May; 137(21):2246-2253.
We examined transplant-free survival and other outcomes at 6 years after the Norwood procedure with a right ventricle-to-pulmonary artery shunt (RVPAS) compared to a modified Blalock‒Taussig shunt (MBTS) in children enrolled in the PHN’s Single Ventricle Reconstruction (SVR) trial. The RVPAS group had similar survival without needing a heart transplant at 6 years but required more catheter interventions before the Fontan procedure. After the Fontan procedure, the two shunt groups had similar rates of transplant-free survival and of catheter interventions, as well as similar right heart function, cardiac symptoms, and complications. However, children in both groups had a steady increase in complications over time; by 6 years, 20% had suffered a blood clot, 15% a seizure, and 7.5% a stroke. These data emphasize the importance of close follow-up and the need to find new strategies to improve the long-term outlook for children with single ventricle anomalies.
P. C. Frommelt, Circ Cardiovasc Imaging. 2019 Feb; 12(2): e007865.
T. A. Miller, Pediatrics. 2019 May; 143(5): e20182577.
C. S. Goldberg, Pediatrics. 2019 Nov; 144(5): e20191010.
C. S. Goldberg, MD. American Heart Journal. 2022 Dec; 254:216-227.
The purpose of this paper is to describe the approach to the long-term follow-up of the Single Ventricle Reconstruction (SVR) cohort through the study familiarly known as SVR III. The original SVR trial aimed to understand what type of surgical connection to the pulmonary arteries worked better for infants with hypoplastic left heart syndrome. The individuals enrolled in the SVR trial were then recruited for long-term follow-up, asked to return at 10-12.5 years for an in person evaluation which included cardiac MRI, echocardiogram, exercise testing and neurodevelopmental assessments. Also, every year, through age 16 years, medical history information was collected. Details of each assessment and the medical history form are included in this manuscript. 74% of the eligible cohort, participated in SVR III. Approaches to engaging patients and families in the study and needed adaptations due to participant age and the COVID pandemic are shared.
J. Detterich. Pediatric Cardiology. 2023 Oct; 44(7):1454-1461.
The Single Ventricle Reconstruction Trial was a first-of its kind randomized surgical trial to determine whether a right ventricle to pulmonary artery shunt was advantageous to patients with hypoplastic left heart syndrome as compared to the Blalock-Taussig-Thomas shunt. The third follow up study (SVR III) also advanced our understanding of this unique circulation by using magnetic resonance imaging of the heart. This test is the gold standard for assessing myocardial function and flow through the heart but is thought to be too long and places a high burden on the patient to lie still for adequate imaging without sedation. In this paper we demonstrate that this test is feasible, well-tolerated and provides significantly improved information about our patients’ circulation.
W. T. Mahle. The Journal of heart and lung transplantation. 2024 Mar; 43(3):453-460.
In this study, we wanted to see how many children aged 12 years with hypoplastic left heart syndrome had heart failure. We discovered that a little more than 5% of the children experienced major heart failure events, like needing a heart transplant. The good news is that most of these children survived after getting a transplant. Additionally, just over 10% of the children had noticeable heart failure symptoms, such as feeling tired when they walked one block or more.
C. S. Goldberg. Circulation. 2023 Oct 24; 148(17):1330-1339.
Treatment for children with hypoplastic left heart syndrome (HLHS) includes an operation on the heart in the first days of life and then subsequent procedures later in infancy and in the preschool years. One of the steps of the first procedure is to provide a source of blood flow to the lungs. Between 2005 and 2008, through the Single Ventricle Reconstruction (SVR) Trial, infants with HLHS received either a shunt from a branch of the aorta to the pulmonary arteries, called a modified Blalock-Taussig-Thomas shunt (mBTTS) or a connection from the right ventricle to the pulmonary arteries (RVPAS). Early data suggested that those infants who had the RVPAS had better survival in the first year of life. We continued to follow these infants over time. Through this study, affectionately known as the SVR III study, we aimed to evaluate if longer-term outcomes by early adolescence, including survival without needing a heart transplant, heart function, exercise tolerance and complications such as the risk of arrhythmias, are affected by the way the first operation was performed, with a mBTTS or an RVPAS.
Among 549 participants enrolled in the SVR Trial, 237/313 (76%) transplant-free survivors participated in SVR III. We found that just about 60% of the original group enrolled in the SVR Trial were alive with their original heart, and that, by 12 years, there was no difference in survival between those who received a mBTTS or RVPAS. Heart function as measured by cardiac MRI and by echocardiogram, on average, were mostly in the normal range and there was no difference between the two treatment groups. Bicycle exercise testing did not differ between the treatment groups either, but, on average, the children in our study had exercise performance which was lower than in children without heart disease. We found that children in this study continued to be at some risk for complications, such as arrhythmias, strokes and protein losing enteropathy into adolescence. Although we compared many factors, the only differences we found between the surgical treatment groups (mBTTS vs. RVPAS) was some increase in the risk for protein losing enteropathy and a greater need for catheterization intervention for those who had received a RVPAS compared to those who received a mBTTS.
Since, for the most part, it didn’t seem to matter if a mBTTS or an RVPAS was used at the time of the first operation, we tried to understand the factors that did influence heart function and those that were associated with transplant -free survival, but we were unable to find any treatment approaches which meaningfully predicted outcomes.
We concluded that, by 12 years of age, shunt type had minimal effect on transplant -free survival, heart function, exercise performance, and complication rates. Heart function was preserved in most transplant-free survivors. Given sub-optimal transplant-free survival, reduced exercise performance and ongoing risk for complications, innovative strategies to improve long-term outcomes for patients with HLHS are needed.
V. Schmithorst. Diagnostics (Basel). 2023 Apr 30; 13(9):1604.
Children born with heart disease can be at risk for problems with development and quality of life. We describe a study of children age 10-12 with hypoplastic left heart syndrome who had Fontan surgery and were participating in the Single Ventricle Reconstruction III Study. The goal was to obtain images of the brain and compare them to healthy children (not born with heart disease) and look for associations with mental abilities, behavior, demographics, and medical factors. The study faced some challenges: (1) coordinating brain imaging for participants already undergoing extensive testing in the main study, (2) recruiting healthy participants for comparison, and (3) the COVID-19 pandemic. Challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) using research registries and advertising the study to community-based groups.
The purpose of TEAM 4 Growth RCT is to learn whether passive range-of-motion exercises can help babies with Hypoplastic Left Heart Syndrome or other single right ventricle anomalies grow better, help their brains develop, and bones be stronger.
L. M. Lambert, International Journal of Cardiology. 2022 Jul 15;359:28-34.
This is the first Udenafil study in children or teens that have had Fontan surgery. This study aimed to learn about the possible benefit of Udenafil for children who have had a Fontan operation and to determine which dose of Udenafil is best.
D. Goldberg, Am Heart J. 2017; 188:42-52.
The purpose of this study was to identify a safe dose of udenafil in teens with single ventricle heart disease. The participants were assigned to placebo or once-a-day or twice-a-day dosing, at different strengths. The 87.5 mg twice-a-day dosing regimen was well tolerated and showed the most consistent drug levels in the blood. This dose was used for the phase III FUEL (Fontan Udenafil Exercise Longitudinal) clinical trial.
This study was done to help us understand why there might be errors in measurements and the true change in heart function values over time.
S. Colan, J Am Soc Echocardiogr 2012; 25:842-54.
C. Lee, Pediatr Cardiol 2014; 35(4):658-67.
K. Molina, Circ Heart Fail 2013; 6(6): 1214–1222.
R. Margossian, J Am Soc Echocardiogr 2015; 28(5):549-558.
S. Reddy, Pediatr Res. 2015 Feb; 77(2): 363–369.
M. K. Friedberg, J Appl Physiol 2016; 120(11):1301-1318.
E.S. Selamet Tierney, Circ Cardiovasc Imaging 2017; 10(11). pii: e006007.
There are multiple echocardiographic methods in common clinical use for measuring left ventricular size and function. Clinical management is often based on both individual evaluations and longitudinal trends, but it is generally not possible or practical to have the same personnel perform and interpret the echocardiographic assessment over time. Using data from the PHN’s, Ventricular Volume Study in children with dilated cardiomyopathy, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the most reproducible method for both individual and sequential evaluations. Compared to dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. In an era in which left ventricular function is not assessed routinely by volume methods (i.e., ejection fraction) in many pediatric echocardiographic laboratories, this study provides important information on reproducibility that could impact long-term management of pediatric dilated cardiomyopathy.
G. Baker, J Am Soc Enchocardiogr 2008; 21(3):230-233.
“Dyssynchrony” means that parts of the heart do not squeeze at the same time. This causes less efficient ejection of blood and contributes to heart failure. There is little data on dyssynchrony in children. This small study looked at whether 3-dimensional echocardiography (heart ultrasound) can be used to identify dyssynchrony in healthy children and children with poor heart function. The results show that 3D echocardiography can be used to look at dyssynchrony in children, and that patients with poorer heart function have more dyssynchrony.