Heart Failure in Pediatric Patients With Congenital Heart Disease

Abstract

Heart failure (HF) is a complex clinical syndrome resulting from diverse primary and secondary causes and shared pathways of disease progression, correlating with substantial mortality, morbidity, and cost. HF in children is most commonly attributable to coexistent congenital heart disease, with different risks depending on the specific type of malformation. Current management and therapy for HF in children are extrapolated from treatment approaches in adults. This review discusses the causes, epidemiology, and manifestations of HF in children with congenital heart disease and presents the clinical, genetic, and molecular characteristics that are similar or distinct from adult HF. The objective of this review is to provide a framework for understanding rapidly increasing genetic and molecular information in the challenging context of detailed phenotyping. We review clinical and translational research studies of HF in congenital heart disease including at the genome, transcriptome, and epigenetic levels. Unresolved issues and directions for future study are presented.

Keywords: cardiovascular malformation; genetics; mutation; single ventricle; stem cell; ventricular dysfunction.

Figure 1. Model of the relationship of heart failure to congenital heart disease and cardiomyopathy

Three phenotypes are shown: CHD (yellow), CM (blue), and CHD with CM (brown). Cardiomyopathy by definition results in ventricular dysfunction in 100% of cases. CHD results in ventricular dysfunction in approximately 20% of cases, while coexisting CHD and CM results in ventricular dysfunction in 100% of cases. HF results in ~65%, 6% and ~40% respectively. Ventricular dysfunction, either systolic or diastolic, precedes HF and therefore offers opportunities for early intervention. Causes of HF may vary despite common clinical features (different colored arrows).

Figure 2. Genes causing congenital heart disease and cardiomyopathy form a complex network

The network diagrams were generated using ToppCluster (www.toppcluster.cchmc.org) software. Gene lists were derived from clinically available next generation sequencing panels for cardiomyopathy (n=50) and CHD (n=44). A) Abstracted cluster network showing a selected subset of features from the following categories: Gene ontology (GO) GO: molecular function; GO: biological processes; GO: cellular component; human phenotype; mouse phenotype; pathway; disease (cardiomyopathy, CHD). The features are color coded by category and connected to cardiomyopathy (white circle ) and CHD gene nodes. B) Gene level network with nodes (blue) selected from features in GO: biological processes category. The network illustrates that regulation of cellular component of movement, actin filament-based processes, and cardiac chamber morphogenesis are shared in common between cardiomyopathy and CHD genes, whereas regulation of force of heart contraction and tube development are unshared.

Figure 3. Schematic of the interactions between causal, predisposing and contributing factors that result in congenital heart disease and heart failure

The figure depicts that CHD has a genetic cause and additional genetic components that predispose the heart to maladaptive responses to environmental factors and may, individually or synergistically, lead to a mismatch between cardiac output and demand with subsequent decompensation and ventricular dysfunction (yellow arrow). This in turn triggers epigenetic modifications as well as a number of metabolic, molecular and neurohormonal compensatory responses, which are also under primary genetic regulation and therefore may predispose to disease. The effectiveness of these responses is a critical determinant of the progression to HF. The signs and symptoms of HF are also subject to individual genetic variation; individual genetic and epigenetic variation can provide protective or deleterious effects that influence severity. HF leads to the institution of medical therapies and surgical interventions, including transplantation, which provide an additional layer of individual variation due to differential pharmacogenomics and molecular responses to the stresses of surgery. ECM, extracellular matrix; RAAS, renin-angiotensin-aldosterone system.