Introduction
The American Heart Association (AHA) established the Science and Clinical Education
Lifelong Learning committee to oversee the various channels of the AHA/American Stroke
Association's robust learning enterprise, which includes scientific meetings, professional
education online learning, spotlight series, journals, and journal webinars. As a
part of this learning enterprise, the Science and Clinical Education Lifelong Learning
committee of the Council on Cardiovascular Diseases of the Young embarked on writing
“The Year in Review” compilation highlighting the scientific progress made in the
pediatric cardiology and cardiac surgery community between May 2016 and May 2018.
The purpose of this article is to highlight 1 to 2 original research or guideline
publications that have been the most impactful and innovative in the various areas
of pediatric and adult congenital cardiovascular research that have the potential
to dramatically change pediatric and adult congenital cardiovascular care and outcomes.
Experts in the field were invited from the Council on Cardiovascular Diseases of the
Young committees to focus on the following categories: congenital cardiac defects
including imaging, electrophysiology, cardiac intensive care, interventional cardiology,
heart failure/transplantation, and pulmonary hypertension, congenital cardiothoracic
surgery, rheumatic fever/endocarditis/Kawasaki's disease, adult congenital heart disease
(CHD), basic science research, preventative cardiology, and early career and mentoring.
Among the many worthy recent publications across pediatric cardiology, the authors
summarized the following papers.
Advances in Cardiac Imaging
Fetal echocardiography is an invaluable tool for the identification of CHD, and is
critical to the preparation of the medical team and family for postnatal care. While
considerable ongoing efforts target diagnostic rates, Bensemlali and colleagues1 identified
significant issues in diagnostic accuracy. Among the 1258 patients reviewed, there
was a 29.3% discordance of pre‐ and postnatal diagnosis leading to a major change
in the planned neonatal treatment in 10.6% of cases. These discordances also led to
changes in planned care beyond the neonatal period in 4.9% of cases: more complex
CHD that was deemed unsuitable for biventricular repair, need for additional surgeries,
increase in the complexity level of the Aristotle score, and unplanned compassionate
care. Continued efforts to improve the accuracy of prenatal diagnosis of CHD are needed.
Three‐dimensional echocardiography is now integrated into most clinical laboratories.
Simpson and colleagues2 provided an expert consensus document about the use of 3‐dimensional
echocardiography in the setting of CHD with a focus on technical considerations, image
orientation, procedural guidance, and functional assessment. This report serves as
an important reference for the field as the technology matures to the point of routine
use.
Cardiac magnetic resonance imaging continues to provide new insights on cardiovascular
disease through tissue characterization. Axelsson and colleagues3 used late gadolinium
enhancement to identify myocardial replacement fibrosis in children with hypertrophic
cardiomyopathy. Late gadolinium enhancement was noted in almost half of subjects with
overt hypertrophy. In those with serial measurements over 2.5 years, late gadolinium
enhancement, left ventricular mass, and left atrial size increased, thereby providing
insight in understanding disease course.
Challenging Existing Knowledge of Wolf‐Parkinson‐White and Brugada Syndrome
This year, 3 articles advanced our understanding of Wolf‐Parkinson‐White and Brugada
syndromes, challenging existing knowledge and provoking new thoughts about current
paradigms for treatment and management of these diseases.
Practice guidelines for management of Wolf‐Parkinson‐White in children have largely
been based on the assumption that risk of sudden death is both predictable and ascertainable.
A large retrospective multicenter international study of 912 children with Wolf‐Parkinson‐White
provided evidence to suggest that, while risk of sudden death in children remains
low, the ability to identify those at highest risk remains difficult.4 These findings
raise questions about future management recommendations and will likely affect the
manner by which physicians counsel patients in the future.
Brugada syndrome has classically been considered a primary ion channel disorder. Although
small case studies had previously suggested ablation as a curative therapy, multiple
studies this year provide further evidence that epicardial ablation may successfully
treat ventricular arrhythmias associated with Brugada syndrome in symptomatic adults.5
While long‐term follow‐up following ablation is lacking and studies in children have
not been performed, these preliminary results provide new insights into this disease.
Regardless of whether ablation is found to be a treatment option for children with
symptomatic Brugada syndrome, the manner in which we approach this disease and counsel
patients regarding long‐term prognosis is likely to change.6
Intensive Care Medicine: Temperature Control After Cardiac Arrest and Management of
Hyperglycemia
Management strategies in cardiovascular intensive care have historically relied on
evidence from adult studies or, at times, from expert opinion. Recent large multicenter
randomized trials in pediatric patients highlight the importance of evidence‐based
trials in our patients and the need to challenge existing care paradigms.
Early clinical trials in comatose adults with out‐of‐house ventricular fibrillation–related
cardiac arrest supported the use of mild hypothermia to improve neurologic outcome.
The recommendation for therapeutic hypothermia was frequently extrapolated to pediatric
patients who had experienced out‐of‐hospital and in‐hospital cardiac arrest. In the
multicenter THAPCA trial (Therapeutic Hypothermia After In‐Hospital Pediatric Cardiac
Arrest), children at 37 centers who experienced in‐hospital cardiac arrest were randomized
to normothermia or mild hypothermia for 48 hours.7 The primary outcome was survival
to 12 months. The trial was terminated because of futility after 329 patients had
been randomized, with no difference in neurologic outcomes between groups. There was
also no difference in secondary outcomes including the use of blood products, serious
adverse events, or mortality at 28 days and 1 year. Based on these findings, newer
recommendations are to maintain normothermia in pediatric patients following in‐hospital
cardiac arrest.
In the PALISI‐sponsored HALF‐PINT (Heart And Lung Failure ‐ Pediatric INsulin Titration)
trial from 35 institutions, critically ill pediatric patients with hyperglycemia (excluding
cardiac surgery) were randomized to tight glucose control (80–100 mg/dL) or a more
liberal strategy (150–180 mg/dL). The primary outcome was number of intensive care
unit (ICU)–free days to day 28. The study found no benefit to tight glycemic control
and the study was stopped early because of futility and possible harm. No significant
differences were seen in the primary outcome or in secondary outcomes of mortality,
ventilator‐free days, or severity of organ dysfunction.8 Interestingly, patients in
the tight control group had a higher incidence of infections. These findings support
a more liberal glucose goal in critically ill pediatric patients.
Novel Interventional Catheter‐Based Techniques and Technologies
A tenet in the field of pediatric interventional cardiology is the exploration of
new techniques and technologies to offer alternatives to surgical therapies.
To date, transcatheter pulmonary valve technologies have been designed for patients
with a circumferential right ventricle to pulmonary artery conduit, leaving the majority
of patients with dilated right ventricular outflow tracts without a device specifically
designed for their heterogeneous anatomies. The new Harmony transcatheter pulmonary
valve (Medtronic, Minneapolis, MN) is a self‐expandable device, designed to accommodate
the dilated right ventricular outflow tract.9 In a US Food and Drug Administration–approved
early feasibility study, 20 Harmony valves were implanted in patients at a median
age of 25 years; nearly all of these patients had tetralogy of Fallot with severe
pulmonary regurgitation. The procedural success rate was 95% with good valve function
by echocardiography at 6 months follow‐up. Long‐term outcome assessment is required,
as is the introduction of a wider variety of device types and sizes.
Infants with ductal‐dependent pulmonary blood flow have traditionally been palliated
with a Blalock‐Taussig shunt. Recently, stenting of the patent ductus arteriosus has
become more commonly used. However, a balanced comparison of Blalock‐Taussig shunt
and patent ductus arteriosus stent as treatment options was lacking. Multicenter studies
from the National Congenital Heart Disease Audit in the United Kingdom10 and from
the Congenital Catheterization Research Collaborative11 reported no difference in
death or unplanned reintervention between Blalock‐Taussig shunt and patent ductus
arteriosus stent. However, the patent ductus arteriosus stent group had lower adjusted
length of intensive care unit stay, less diuretic use, and fewer procedural complications.
A high level of scrutiny and rigor should continue to be applied to all interventional
therapies emerging from the cardiac catheterization laboratory.
Innovations in Heart Failure and Heart Transplantation Medicine
Recent innovations in pediatric heart failure are highlighted by the ever‐growing
and highly adaptive use of mechanical circulatory support. The Second Pedimacs Registry
report provides the most comprehensive, contemporaneous data on ventricular assist
device (VAD) indications for children with heart failure.12 While these devices are
still primarily used as a bridge to transplant, outcomes by patient age/size and device‐type
vary significantly. Adolescents and children 6 to 10 years of age, in whom implantable
continuous devices predominate, experienced lower morbidity and mortality compared
with infants and children <6 years old, in whom paracorporeal devices (both pulsatile
and continuous) predominate. Other key findings included the increasing use of VADs
to support children with CHD, including many with single‐ventricle anatomy (62% of
CHD), and an inferior 6‐month survival (48%–60% versus 80% for cardiomyopathy). Overall
these data highlight a clear need for better strategies/devices for small patients
and those with CHD. “Temporary” VADs (eg, CentiMag/PediMag, Rotaflow) may also be
successfully used for support from weeks to months in children with CHD, cardiomyopathy,
or retransplant, including many who are small (<5 kg). Temporary VADs provided longer
survival than extracorporeal membrane oxygenation for children awaiting heart transplantation.13
Finally, in an innovative multicenter analysis of racial disparities in pediatric
heart transplantation outcomes (530 recipients, 6 US centers), Green et al analyzed
clinical data and data on allelic variations across 20 genes involved in allograft
immune responses.14 After adjusting for clinical and genetic differences associated
with rejection, graft loss, and death, black race remained a significant predictor
of adverse outcomes, with large hazard ratios (1.58–3.13), suggesting that societal
implications of race also influence pediatric heart transplantation outcomes.
Congenital Cardiothoracic Surgery
With the high prevalence of neurodevelopmental delays and the impact on quality of
life, the surgical focus has shifted to collaborative research on long‐term morbidity.
The International Cardiac Collaborative on Neurodevelopment assessed factors associated
with neurodevelopmental outcome in children undergoing cardiac surgery.15 Patient
and preoperative factors impacted 30% of the variability in Psychomotor Development
Index and Mental Development Index of the Bayley Scales of Infant Development. Longer
cardiopulmonary bypass duration in infants undergoing cardiac surgery was associated
with lower Psychomotor Development Index and Mental Development Index, while deep
hypothermic circulatory arrest and regional cerebral perfusion were not predictive.
In the postoperative period, significant predictors of lower Mental Development Index
included extracorporeal circulation membrane oxygenation/VAD use and longer length
of stay. After adjusting for patient and perioperative factors, intraoperative and
postoperative factors accounted for only 5% of the variance in scores. The current
study re‐emphasizes the importance of patient and preoperative factors (30% versus
5%) to neurodevelopmental outcomes. The study did not identify any factors that could
be modified during the intraoperative or postoperative period.
The landmark Single Ventricle Reconstruction Trial was the first and only randomized
controlled trial in congenital heart surgery evaluating the impact of shunt type on
transplant‐free survival for single ventricle patients.16 The study was notable for
a survival advantage with the right ventricle to pulmonary artery shunt at 1 year.
However, by 6 years, the early survival advantage of the right ventricle to pulmonary
artery shunt did not persist. This trial has demonstrated through repeated interim
analyses and long‐term follow‐up that the conclusions from this cohort are dynamic.
Thus, the perpetuation of long‐term data on congenital heart surgery patients is essential
to our understanding of these surgical strategies. The current update sadly shows
that despite the most recent innovations, only 60% of patients with single right ventricle
heart lesions are alive and free of transplant at 6 years.
Rheumatic Fever, Endocarditis, and Kawasaki Disease
Global Burden of Disease estimates in August 2017 revealed that 33.4 million persons
have rheumatic heart disease (RHD).17 Despite this, RHD research has remained largely
neglected.
Echocardiography can detect RHD before symptoms develop (latent RHD). In 2012, echocardiographic
screening for latent RHD was named among the AHA's “Top 10 Advances in Cardiovascular
Disease and Stroke.” However, deployment of echocardiographic screening has stalled
as the impact of early case detection remains unclear. In a longitudinal outcomes
study (median 2.3 years) in 227 Ugandan children with latent RHD,18 those children
with moderate‐to‐severe latent RHD had poor outcomes; 47.6% progressed and 2 died.
Children with mild latent RHD had more heterogeneous outcomes, but were at risk of
progression (10%–25%). Importantly, these data were insufficient to determine whether
penicillin prophylaxis (penicillin G) improved outcomes, providing the critical stimulus
for the GOAL (Gwoko Adunu pa Lutino) trial, currently in progress to determine the
impact of penicillin in latent RHD.
Adult CHD
With the dramatic improvement in survival for children and adolescents with CHD, there
are now more adults living with CHD than children. Despite this shift in demographics,
there are limited studies on long‐term outcomes in adults with CHD. Utilizing long‐term
regional/national databases and establishing multicenter research networks have allowed
investigators to generate meaningful long‐term outcomes data.
Patients with CHD may undergo a significant number of imaging procedures (eg, cardiac
catheterizations, chest radiographs, and computed tomography) utilizing ionizing radiation
over their lifetime. While low‐dose ionizing radiation theoretically conveys a low
risk of developing cancer, it is difficult to determine the cumulative effects of
multiple exposures. Utilizing the Quebec CHD database, Cohen et al demonstrated that
CHD patients with a higher ionizing radiation exposure had a cancer incidence of 8.5%
versus 3.3% in CHD patients with lower exposure with an odds ratio of 1.10 (95% confidence
interval, 1.05–1.15) per 10 mSv.19 After controlling for age, sex, CHD severity, comorbidities,
surgical history, and competing risk of death, patients with high exposure were found
to be at a 2.4‐fold greater risk of developing cancer than the low‐exposure group.
The study sets the stage for further prospective studies that will ultimately guide
radiation policy recommendations and regulations in CHD patients.
Most quality‐of‐life studies performed in the CHD population do not account for cultural
or geographical determinants. APPROACH‐IS (Assessment of Patterns of Patient‐Reported
Outcomes in Adults with Congenital Heart Disease—International Study) is a cross‐sectional
study that evaluated quality of life in 4028 adults with CHD, from 15 countries across
5 continents utilizing a uniform research methodology.20 Quality of life among adults
with CHD was generally good, and varied more with patient characteristics than country‐specific
factors. Based on these results, the authors proposed that uniform criteria could
identify CHD patients with poorer quality of life regardless of geographical location.
Stem Cell Therapy and Genome Editing
The emergence of novel technologies using human induced pluripotent stem cells and
genome editing are unique opportunities for studying cardiovascular disease related
to development, mechanism of disease, drug toxicity, and therapies to enhance the
regenerative capacity of the heart.
There are limited stem cell–based clinical trials in patients with CHD, and these
primarily focus on hypoplastic left heart syndrome. The PERSEUS randomized phase 2
controlled trial used cardiac progenitor cell infusions to treat univentricular heart
disease. Intracoronary cell infusions were performed followed superior cavopulmonary
connection and modified Fontan procedures and demonstrated the safety of this approach.21
While cardiovascular regenerative medicine has yet to transform our practice, the
future holds great promise.
Genome editing is targeted, genetic modification in the human genome and can be done
using transcription activator‐like effector nucleases. Karakikes et al designed transcription
activator‐like effector nucleases constructs to knock out human genes associated with
cardiomyopathies and CHDs.22 As proof of concept, a pathogenic mutation causing dilated
cardiomyopathy (TNNT2 p.R173W) was selectively knocked out using transcription activator‐like
effector nucleases in patient‐specific inducible pleuripotent stem cell‐derived cardiac
myocytes, rescuing the dilated cardiomyopathy phenotype in vitro. In addition, Holt‐Oram
syndrome was modeled in inducible pleuripotent stem cell‐cardiac myocytes in vitro
and uncovered novel pathways regulated by TBX5 in human cardiac myocyte development.
Prevention: Ideal Health Behaviors and Factors
The AHA Strategic Impact Goal Through 2020 and Beyond initiative recommends adoption
of 4 ideal health behaviors and 3 ideal health factors that when implemented can prevent
heart disease in 80% of cases. The 4 health behaviors include the following: abstinence
from smoking, maintenance of a body mass index <85th percentile, participation in
60+ minutes of physical activity daily, and adherence to a heart‐healthy diet. The
3 ideal health factors include maintenance of a normal cholesterol, hemoglobin A1c,
and blood pressure. Unfortunately, adoption of these recommendations by American youth
has been abysmally poor. While >80% of youth do not smoke, <1% have an ideal diet.
The prevalence of pre/diabetes mellitus type 2 has increased from 9% to 23% and 11%
of youth have abnormal blood pressure.23 The diagnosis of hypertension is not made
in 77% of youth. The 2017 Clinical Practice Guideline for the Diagnosis and Management
of High Blood Pressure in Children and Adolescents updates definitions and management
strategies and proposes methods for improved recognition of hypertension.24
The National Institutes of Health funded i3C Outcomes Study is the first longitudinal
cohort study to assess the impact of childhood cardiovascular risk factors on adult
cardiovascular end points.25 Results from this study will further our knowledge of
the relationship between childhood factors and adult heart disease.
Early Career and Mentorship
Employment opportunities in pediatric cardiology have been diversifying. The United
States Pediatric Cardiology 2015 workforce assessment survey showed that nearly 60%
of all third‐year graduates pursued additional subspecialty training and nearly 90%
of them accepted academic positions. Greater difficulty in securing positions was
seen in subspecialty areas including cardiac catheterization and electrophysiology.26
There are numerous obstacles to becoming a successful physician‐scientist. The Early
Career Committee of the Cardiopulmonary, Critical Care and Resuscitation Council of
the AHA recommends that mentoring be sought early during training and initial faculty
appointments. Career success requires meaningful mentorship relationships that in
addition to obtaining grant funding can lead to the development of adaptive skills
to the meet demands of academic careers and improve the integration of our professional
and personal lives. A physician‐scientist's long‐term academic success needs to combine
long‐term higher‐risk projects with short‐term low‐risk projects.27
Conclusions
Our scientific knowledge and clinical capabilities in the field of pediatric cardiology
and cardiac surgery continue to expand. Notable reports in the last 2 years challenge
existing paradigms in pediatric cardiology and cardiac surgery (Figure) and encourage
us to identify and address novel risk factors, medical and catheter‐based interventions,
new devices, multicenter randomized clinical trials to change our current practice,
and increase focus and attention on prevention of acquired cardiovascular disease
and regenerative and genomic opportunities. These articles also highlight the need
for collaborative science across the T1 to T4 research paradigm.
Figure 1
Summary of advances in pediatric cardiology and cardiac surgery to challenge existing
paradigms in care.
Disclosures
Reddy, MD—NIH (moderate); US DOD (moderate); Marino, MD, MPP, MSCE—AHA (moderate),
NIH (moderate); Novartis (moderate); medical expert (moderate); Baker‐Smith, MD, MPH—Consultant
for AAP 2014–2018 as epidemiologist and methodologist for the 2017 clinical practice
guidelines for screening and management of high blood pressure in children and adolescents;
Glatz, MD, MSCE—NIH (moderate); Children's Heart Foundation (moderate); Big Hearts
to Little Hearts (moderate); CHD Coalition (moderate); Feingold, MD, MS—NIH/NIAID
(moderate); US DOD (moderate); Other research support: Abbott Diagnostics (significant);
Barth Syndrome Foundation (moderate); Hillman Center for Transplantation at UPMC (moderate);
Novartis (moderate); Honoraria: Stealth Biotherapeutics (moderate). The remaining
authors have no disclosures to report.