Heart Failure in Congenital Heart Disease: Age of Uncertainty

Heart failure (HF) in congenital heart disease (CHD) is vastly different to that observed in acquired heart disease. In this group of patients, more so than others, the cardiac history begins in-utero. Infancy and childhood are commonly punctuated by surgeries and other palliative interventions. By adulthood, the heart has been exposed to a range of events and insults that establish the substrate for myocardial dysfunction. Many patients learn that they are neither fixed nor cured when they experience first-hand the complications of living with CHD, including exercise intolerance, repeat surgeries, valvular dysfunction, infective endocarditis, arrhythmias, thromboembolic events, and, for an increasing number of patients, HF. HF in CHD encompasses a diverse clinical spectrum that may include right ventricular failure, left ventricular failure, biventricular failure, or a failing single ventricle circulation. Comorbidities are common, with arrhythmias in over half and pulmonary hypertension in one-quarter of adults with CHD-related HF.¹ As more children with CHD survive to adulthood, the prevalence of HF is increasing as highlighted by an 83% increase in adult CHD-related HF admissions over the last two decades.² Mortality following a diagnosis of HF in CHD is also high, accounting for roughly one-quarter of deaths in both children³ and adults.^4,5

Despite the importance of HF in CHD, prior HF guidelines have not specifically addressed this patient group.⁶ Presumably, CHD has not been included in past HF guidelines because of the lack of evidence-based therapies and because standard paradigms, such as the ACCF/AHA Stages of HF and associated pharmacologic strategies, do not apply. Readers of the 2013 HF guidelines were referred to “publicly available resources” to address questions relating to HF in CHD, although in reality the evidence base for answering such questions has been limited as have resources for those providing care. Exclusion and/or inadequate identification of CHD patients in HF trials and registries has meant that mainstream HF treatment guidelines and performance improvement programs have not addressed quality of care or outcomes in this population.⁷ In their statement, Stout and colleagues have taken the first step in addressing this knowledge gap. Encompassing HF in both pediatric and adult CHD populations, the authors review HF as it relates to specific CHD lesions: patients with a systemic right ventricle, palliated single ventricle, left-sided pressure overload lesions, and volume loading lesions of the sub-pulmonic right ventricle. Recognizing HF in CHD as a burgeoning field with insufficient data to properly inform clinical practice guidelines, the scientific statement is instead a rigorous review of the existing literature and highlights the challenges and controversies associated with managing HF in this unique context. The knowledge amassed can be considered according to the key clinical milestones that reflect the trajectory of HF in CHD: (1) preclinical myocardial dysfunction, (2) HF diagnosis, (3) HF interventions, and (4) HF mortality.

The substrate for HF in these patients is frequently present at birth with a cascade of insults in childhood and beyond promoting myocardial injury and dysfunction. Three putative routes have been proposed for the development of HF in CHD: (1) rare monogenetic entities that cause both CHD and HF, (2) severe CHD in which acquired hemodynamic effects of CHD or surgery result in HF, and (3) a combined effect of complex genetics and acquired stressors.⁸ A major obstacle to mapping HF signaling pathways in CHD is the heterogeneity seen – not only across the spectrum of lesions but also within defined sub-groups. The congenital heart may be exposed to a range of events and insults that varies over the course of a lifetime, including cyanosis, cardiopulmonary bypass, pressure and/or volume overload, arrhythmia, and ischemia. Functional and molecular adaptations vary over time leading to a shifting mosaic of gene expression and HF signaling pathways. Identifying any single therapeutic target in the midst of these complex interactions is a major challenge. Advances in cardiovascular –omics research, biostatistics, and bioinformatics, bring us closer to building an integrated systems biology view of the genetic, environmental, and sociobehavioral factors that contribute to HF in CHD. Given the relatively high prevalence of genetic defects in patients with CHD and the lack of information surrounding gene-environment interactions (including the impact of cardiopulmonary bypass and surgery), a precision medicine approach⁹ is especially attractive in this population. Yet without a dedicated registry or a standardized nomenclature for CHD-related HF, there is a risk that CHD patients and researchers will not be positioned to benefit from this exciting new phase of scientific discovery.

HF in CHD may be diagnosed at any age. In infants, a diagnosis of HF may coincide with the diagnosis of CHD, with HF severity often proportional to disease complexity. Other than the use of prostaglandins to maintain patency of the ductus arteriosus in a shunt-dependent circulation, pharmacologic interventions do not directly target or address the underlying defect(s). Hence, surgical palliation is the primary strategy for preserving cardiac function and improving survival among those born with CHD. For others, HF will first manifest after congenital heart surgery where it is an important cause of mortality in early childhood.³ In those surviving to adolescence and adulthood, HF re-emerges as an important cause of late morbidity and mortality. A simple comparison of HF hospitalizations confirms this striking difference with admissions in adult patients with CHD (ACHD) being spread evenly across adulthood compared with those with acquired heart disease in whom HF admissions rise steeply after 75 years of age (Figure). For many young adults with CHD, a diagnosis of HF will correspond with other life events, including marriage, children, entering the workforce and no longer being covered by parental health insurance, raising special challenges for patients, families, and care providers alike.

As reviewed by Stout et al, recognizing HF in adolescents and young adults with CHD is a major clinical challenge. Discriminating between inherent physiologic limitations of CHD versus changes secondary to HF is often not possible based upon history, physical examination, and other objective parameters. NYHA Functional Class underestimates the true extent of exercise intolerance in CHD patients, with “asymptomatic” patients having significantly reduced peak oxygen consumption 42% below that of healthy subjects.¹⁰ On physical examination “classic” features of HF, including peripheral and pulmonary edema, are often absent until late in the HF trajectory. Serum BNP is frequently elevated, although cut-off values for diagnosing HF in CHD are not known because studies include mixed populations of CHD subtypes with and without HF. Echocardiography is useful for confirming normal versus severely reduced ventricular function, but is less reliable for identifying more subtle progression from mild to moderate systolic dysfunction especially in complex forms of CHD such as functional single ventricle defects.¹¹ In addition to a global definition that highlights the unique clinical trajectory of HF in CHD we desperately need to establish a lesion-specific taxonomy that has clinical and prognostic relevance. The challenges associated with establishing a common vocabulary for HF in CHD are outweighed by the benefits, which would include an enhanced ability to compare CHD HF outcomes between centers, creating the foundation for future CHD HF registries, and establishing quality improvement programs for CHD-related HF. Definitions for HF in CHD will also be important for working with governments and payers to ensure CHD patients have equal access to HF services including cardiac rehabilitation. In the modern era we cannot rest upon inadequate care or poor outcomes simply on the basis of difference, whether it is due to CHD or otherwise.

Unlike acquired HF in which strategies for protecting and improving ventricular function are drug based, CHD relies heavily upon surgical and other structural interventions to achieve these aims. Invasive assessment is therefore a common starting point, with hemodynamic data serving as a central reference for individualized HF treatment plans. Despite the central role of surgical and other structural interventions in CHD, their impact on HF outcomes has not been directly assessed. The move to multi-center collaborations may facilitate this goal. One recent example is the Canadian Outcomes Registry Late After Tetralogy of Fallot Repair (CORRELATE). The CORRELATE Study will link clinical, imaging, and functional data to compare a range of clinically relevant outcomes in patients with pulmonary regurgitation managed conservatively versus those referred for pulmonary valve replacement.¹² The Australia and New Zealand Fontan Registry recently compared outcomes for centers adopting early versus late conversion for Fontan failure,¹³ demonstrating improved survival free from heart transplantation in those who underwent early versus late Fontan revision. Whether comparisons between centers hold the same validity in the United States, European countries, and other regions is unclear given the influence of fractionated healthcare and socio-geographic variation.

In reviewing the literature to date, Stout et al identify our successes while encouraging us to explore deeper and unite in our commitment to improving outcomes for this growing HF population. Advances in surgical and medical care have led to a new generation of adult survivors with CHD, many of whom harbor the substrate for HF. These are the blue babies, those with holes in their heart, and the miracles who survived being born with one ventricle instead of two. As beneficiaries of major scientific advances, adults with CHD are trail blazers, the living proof of boundaries pushed and convention upturned. As relative newcomers to the HF community, CHD patients pose many unanswered questions for HF and ACHD specialists alike. Improving HF outcomes in CHD patients requires these patients to be recognized not only by congenital heart specialists but a broader coalition of clinicians and researchers dedicated to improving quality of care for all HF patients including those with CHD.