Chronic Heart Failure in Children and Adolescents with Congenital Heart Disease: Removing Failure from our Success.

Over the past decade, the incidence of pediatric heart failure has been steadily increasing. Despite this, evidence-based guidance in the care of pediatric patients with heart failure lags significantly behind that of adults. In 2008, the NIH National Heart, Lung and Blood Institute established the Heart Failure Clinical Research Network. Over 2,000 clinical trials in adult patients are listed on the NIH website, and this large number of trials with robust sample sizes has led to guideline-directed medical therapy that is well backed by scientific data. In contrast, there are only 16 pediatric heart failure trials listed, and only two of these trials were randomized clinical trials of patients with congenital heart disease (CHD). The first began in 2007 and evaluated the use of carvedilol in pediatric patients with heart failure. This study included patients with a structurally normal heart and those with congenital heart disease. ¹ The second study was sponsored by the Pediatric Heart Network (PHN) and evaluated the use of angiotensin -converting enzyme inhibitors in patients with single ventricle heart disease. ² It failed to show any improvement in outcomes. In both studies, the sample size is about 1/10 of the size of similar studies conducted in adults.

In addition to a limited number of studies with small sample sizes, pediatric heart failure research is further challenged by identification of appropriate endpoints. As a result, much of the treatment strategy in pediatric heart failure is simply extrapolated from adult evidence. Recognizing this problem in 2022, the National, Heart, Lung, and Blood Institute developed recommendations for the best way to identify endpoints for pediatric heart failure studies.³ Unfortunately, this has not yet resulted in consensus regarding appropriate endpoints and pediatric clinical heart failure studies remain rare.

Research in the field has become even more challenging over the past several decades as the underlying substrate for pediatric heart failure has also changed. The development of penicillin dramatically decreased the prevalence of rheumatic heart disease in the United States. Hopefully, this will also soon be true in developing countries. The homogenous population of heart failure from rheumatic heart disease has now been replaced by the heterogeneous, rapidly growing population of patients with palliated congenital heart disease.⁴ Despite the label failure, we should be proud that advances in pediatric cardiology now mean that most patients born with congenital heart disease can expect to reach adolescence and adulthood.

Most notable is our population of patients with single ventricle heart disease, particularly those with hypoplastic left heart syndrome (HLHS), a cardiac malformation once uniformly fatal. Strategies have evolved over time from providing comfort care, to offering primary transplant and currently, to completing multiple palliative procedures resulting in Fontan physiology. Over this time course, we have also revised our surgical approach at least three times. Patients are now surviving longer than ever. It is becoming clear that many patients with Fontan physiology will develop heart failure. This is true not only of our HLHS population but of all single ventricle patients with Fontan physiology. Because of these advances, patients with CHD now account for the majority of pediatric patients with heart failure.

The heterogeneity of congenital heart disease makes truly meaningful large clinical trials challenging. Heart failure occurs in both one and two ventricle CHD. Patients with single ventricle physiology can have morphological right, left or indeterminate ventricles. The surgical approaches to these patients have evolved also changed over time. In addition, in some patients, there may be underlying genetic abnormalities, including occasionally an identified cardiomyopathy gene.⁵ Impactful research will require collaboration to allow for an adequately sized cohort to draw meaningful conclusions. As noted above, the Pediatric Heart Network (PHN) has helped formalize and fund collaborative research efforts. This has resulted in Fontan Udenafil Exercise Longitudinal trial (FUEL) and is likely to continue to support important future clinical research.⁶ Many other collaborative quality improvement programs have also collected important data, including the Pediatric Cardiac Critical Care Consortium (PC4) and Pediatric Acute Care Cardiology Collaborative (PAC3), that may be useful in studying these patients. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) is actively collecting data on CHD heart failure patients.

However, what has become clear from these studies and registries is that collaboration alone is not enough. When studying pediatric heart failure in patients with congenital heart disease, we all need to be speaking the "same language" to collaborate more effectively. This common language can then be used to clearly define cohorts and establish meaningful endpoints, which is crucial to drawing accurate conclusions.

The AHA Scientific Statement on the Evaluation and Management of Chronic Heart Failure in Children and Adolescents with Congenital Heart Disease highlights these knowledge gaps. It shares a standard definition of heart failure when referring to systolic ventricular dysfunction. The Statement acknowledges the challenges faced when defining heart failure in a systemic right ventricle or undetermined ventricle. It acknowledges that this is also challenging when defining heart failure with preserved ejection fraction. Important comorbidities that could affect ventricular function and heart failure symptoms are also considered, including cyanosis, arrhythmia, end organ dysfunction, pulmonary hypertension and genetic abnormalities.

Adult heart failure symptoms have routinely been classified by the New York Heart Association and the American Heart Association. It was clear that this classification would not be applicable to infants with heart failure and thus, in 1992, Robert Ross and colleagues developed the Ross Classification to address this need. Initially, it consisted of four stages defined by feeding, respiratory symptoms and growth. It has now been modified several times to be applicable to a wider range of ages. A recent modification proposed by Dr. Ross includes additional factors used to diagnose heart failure including biomarkers, growth, hepatomegaly and AV valve insufficiency. ⁷ In this Scientific Statement, Amdani and colleagues propose a separate classification for severity of heart failure in patients with structural heart disease. Like the modified Ross classification, it includes biomarkers and growth. In addition, it encompasses exercise capacity, cardiac index, and number of hospitalizations. AV valve insufficiency and hepatomegaly are not considered, as these are present in many of single ventricle patients without heart failure symptoms. The challenge remains that many of the included factors vary based on patient age and the presence of Fontan physiology. If widely adopted, many modifications are likely to follow.

The Scientific Statement also proposes new definitions of heart failure stages for this patient population. These stages consider the other comorbidities that affect patients with congenital heart disease, including arrhythmias, cyanosis, and pulmonary hypertension as well as changes in biomarker measurements. Clearly defining heart failure severity and stages in patients with congenital heart disease may be the statement's most important contribution. It provides a uniform way to evaluate symptoms and, in doing so, provides a potential tool to measure the effectiveness of our interventions. The importance of this cannot be overstated. Even with objective measures that a therapy is working, if the patient does not feel better, the value of that therapy remains questionable. Also included in these stages are clinical considerations for therapy. This inclusion reflects the approach utilized by many pediatric heart failure professionals. Not surprisingly, many of these suggestions are extrapolated from adult studies without robust evidence in pediatric patients or patients with congenital heart disease.

The Scientific Statement concludes with a suggested protocol for follow up of pediatric patients with congenital heart disease and heart failure, including general suggestions on intervals, consultations, and testing. The utility of the suggested protocol for following these patients that will potentially serve as a general overview for care. It begins to lay the foundation for more effective clinical research in heart failure in patients with CHD. It helps to harmonize the definitions of heart failure in these patients and emphasizes the knowledge gaps in our understanding of these patients and their cardiac function. Hopefully, this will highlight the need for further research in this population and make future studies easier to conduct. It has clearly been shown that the pathophysiology of pediatric patients with congenital heart disease is vastly different from their adult counterparts with heart failure, and therefore, it is imperative that we develop novel modes of treatment and that data from adult heart failure patients is not empirically applied without well designed and powered pediatric studies to ensure no harm is done. For the past century, the American Heart Association has improved life and given hope to patients with congenital heart disease. It supported Helen Taussig's work on "blue babies", before she later became the first female AHA president. It supported Dr. Rashkind when he developed a new technique to create an atrial septal defect in the catheterization lab. More recently, it has supported Scientific Statements and Guidelines to improve the care of patients with CHD. Topics addressed have included the care of adults with congenital heart disease, transition of care from pediatric to adult health care professionals and care of the patient with a Fontan circulation, to name a few. The need for scientific statements on adults with congenital heart disease was unimaginable when Dr. Taussig and Dr. Rashkind were making their contributions to the field. Since that time, there has been enormous progress in the field of pediatric cardiology. We must now take the failure out of those successes. Hopefully the framework provided, and knowledge gaps outlined in this Scientific Statement will make that goal easier to achieve.