Regardless of the injury to the heart, be it by infarction, infection, toxin, genetic abnormality, hypertension or valve disease, a common syndrome can develop that is characterized by progressive exercise limitation and neurohormonal activation, and so it might be more helpful to view HF as a continuum from asymptomatic ventricular dysfunction with modest neurohormonal activation to severe ventricular dysfunction with symptoms at rest and marked neurohormonal activation (3).

HF in congenital heart disease is a combination of inherited factors and acquired stressors. Rather than due to the loss of myocites due to myocardial infarction or by inherited intrinsic abnormalities in myocardial cells, HF in these patients is most probably sculpted over many years by persistent abnormalities in cardiac pressure and/or volume (3). Literature, quite silent on the topic for a long while, has now shown a significant progress in the field showing that neurohormonal activation is present in grown up congenital heart disease (GUCH), both in symptomatic and asymptomatic patients (4). There is sufficient data showing that patients with complex congenital heart disease, even if surgically repaired, often have elevated B-type natriuretic peptide (BNP) levels that correlate both with NYHA Class and mortality (5-7))). Not only that, but neurohormonal activation in GUCH bears the hallmarks of chronic heart failure, increasing in relation to the symptom severity and ventricular dysfunction and not necessarily connected to the anatomic substrate (4).

Current estimates place the ever expanding population of adults with congenital heart disease at 1.2 million in Europe and around 1 million in USA alone (8, 9). This is the result of major advances in cardiothoracic surgery and pediatric cardiac care over the last five decades. Unfortunately, when those patients reach adulthood, they still face and increased risk of death compared to the general population (10). When we take the look at the CONCOR Registry which assessed the risks and causes of the increased mortality in GUCH patients, we find that HF is the leading cause of death (11). The probability of HF appearing increases with age and is dependent on the original defect with single ventricles, Tetralogy of Fallot (TOF) and transposition of great arteries (TGA) having the greatest risk (11, 12).

Symptoms are quite frequent in this population with around 25% of Fontan patients symptomatic 10 years following procedure (13), 75% of unoperated congenitally corrected TGAs presenting symptomatic (14), and 79% of patients with complex congenital heart disease having NYHA Class II or higher limitation in functional capacity (4). On the other hand, GUCH patients are often asymptomatic or claim no symptoms due to the fact that living with symptoms has been a lifetime constant so little attention is attributed to minor variations in exercise tolerance (15).

Looking at several exercise studies performed in adult patient groups with more complex congenital disease, although patients with symptoms have significantly reduced exercise capacity compared to patients without symptoms, both groups have significantly lower exercise tolerance and cardiovascular capacity compared to the healthy population (16-18). Looking at Figure 1 we see that the difference between preclinical and clinical failure in this population is exclusively marked by the presence or absence of symptoms, but not much else.

If we take into account that in many accounts HF in GUCH mimics congestive HF from other causes, we might draw the conclusion that we should approach the treatment in the same way. If we look at the cornerstones of medical therapy according to the current guidelines, the beta-blockers, ACE inhibitors, angiotensin receptors blockers and mineralocorticoid receptor antagonists, their results in GUCH patients significantly differ compared to the general HF population. First of all, these kind of patients where unanimously excluded from all the major randomized controlled trials of all of there drugs. Further on, there are now a host of, albeit small, randomized and controlled trials that have failed to show a significant clinical benefit of these therapies in congenital heart disease (19-24).

When looking at the failure of systemic morphologically left ventricle it may be reasonable to follow current HF guidelines (25), but in the case of a failing systemic right ventricle or a single ventricle morphology studies have not been as supportive in the case of all of those drugs except for beta-blockers that show some positive RV remodeling, symptom reduction and exercise tolerance increase, but the numbers in the studies were insufficient to show any mortality benefit (26-28). The underlying problem is probably that just targeting the neurohormonal pathways is largely insufficient if we are dealing with a multitude of factors that influence the performance of said ventricle. For example, in this very interesting study by Derrick et al it has been shown that in patients after atrial redirection procedure a fall in stroke volume during exercise or dobutamine infusion was a consequence of of impaired atrioventricular transport rather than right ventricular systolic failure (29). Furthermore, in patients with congenitally corrected TGA, those with significant systemic (tricuspid) valve insufficiency was a significant predictor of RV dysfunction and mortality (30). Both of those findings support the notion that in these patients further afterload reduction with medical therapy could be a flawed target of intervention in the short term, and surgical/interventional procedures should be considered. A broad overview of therapeutic approach is presented in Figure 2.

The main underlying pathologies for heart transplantation (HTx) in adult congenital heart disease are systemic right ventricles, univentricular heart with or without Fontan circulation, and tetralogy of Fallot (31). They constitute a fairly small number of overall cardiac transplant patients with International Society for Heart and Lung Transplantation (ISHLT) Registry reporting around 2% of heart transplant cases falling inside this cathegory (32).

Timely identification of possible candidates for HTx is essential, and in patients with acquired heart disease, maximal oxygen consumption per unit time (V_O2) has been used as an important criterion for listing for transplantation. Traditionally maximum of <12–14 mL/kg/min has been used as a cutoff value. It has also been shown in GUCH patients that reduced V_O2 is associated with increased risk of hospital admission and death (33, 34) and self-reported exercise tolerance poorly correlated with objective measures of exercise capacity (35). Huge problem in this method is that many patients start their clinical journey with a reduced V_O2 compared to the normal population and maintain levels which are quite close to what would be expected in HTx candidates while symptomatically fine (16), and self-reported excercise tolerance poorly correlates with objective measurements of exercise capacity (35). Another marker that we might fall upon, BNP, has the potential to be very valuable since it has been shown to predict sudden cardiac death and ventricular arrhythmias even in GUCH patients not presenting with HF and temporal increases in BNP concentration have been found to predict mortality (36, 37). Therefore, it would be prudent to perform serial standardized exercise testing and BNP measurements in long-term follow-up of GUCH patients. Some other factors, such as anemia, hyponatremia and renal dysfunction have been identified as risk markers for mortality in GUCH patients, as are pulmonary hypertension, recurrent hospital admissions for heart failure and cardiac cahexia (38-40).

Furthermore, if these patients undergo HTx, the risk of complications is significantly higher than in normal HTx and patients with previous Fontan, classic Glenn or any kind of univentricular heart that has previously undergone cardiac surgery are at an even more increased risk of perioperative morbidity and mortality (41). Patients with an irreversible pulmonary hypertension (fixed PVR index of >5 WU/m² or a transpulmonary gradient >15 mmHg not responsive to vasodilator therapy) may be candidates for combined heart-lung transplantation (42). Whatever the plan, early involvement of congenital heart cardiac surgeons is crucial in assessing the risk and the transplantation should be performed by a surgeon experienced in congenital heart surgery. Although mortality in early postoperative period is higher, long-term mortality falls in line with other types of heart transplant candidates (43).

Treatment of GUCH patients with clinical aspects of HF remains challenging. Medical therapy remains unproven, and while general HF guidelines can be extrapolated on patients with the failure of the morphologic left ventricle, patients with a failure of morphologic right ventricle or single ventricle morphology behave differently. Beta-blocker therapy remains as the only one with any proven benefit in those patients. HTx, although viable alternative, is fraught with perioperative and early postoperative mortality, while determining the right timing for enlisting patients on the heart transplant list remains a challenge.

The future needs to address the question of optimal medical therapy with controlled randomized studies in selected subgroups of patients with GUCH without hoarding different congenital morphologies with most likely different causes of HF to reach adequate numbers. Device therapy also holds promise in these patients. Cardiac resynchronization therapy might be helpful in failing ventricles with long QRS complexes like those often found in patients with ccTGA or atrial switch TGA, but until any kind of study is performed, it’s use remains unproven. Ventricular assist devices are now used more and more in children as a bridge-to-transplant solution but need more experience in adults, as well as specific subset of surgical skills not found in most surgical centres, and are mostly designed for the support of a morphologic left ventricle.