In conjunction with surgical or interventional repair of residual anatomic lesions, medical treatment is always proposed to ACHD patients with HF.

HF with reduced ejection fraction (HFrEF) of the morphologic left ventricle (LV) is defined as an ejection fraction (EF) of 40% or less [2], and this seems to be also applicable to ACHD. ACHD patients have typically been excluded from adult HF clinical trials, and there are no trials with hard clinical endpoints pertaining to ACHD patients. Therefore, international guidelines suggest that diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor/neprilysin inhibitors, mineralocorticoid receptor antagonists, βblockers, and now sodium-glucose cotransporter-2 inhibitors should be used in this population [2]. There is theoretical evidence to support the use of angiotensin converting enzyme inhibitors and, if not tolerated, angiotensin receptor blockers in the treatment of asymptomatic or symptomatic HF ACHD patients. Similarly, the evidence for using β-blockers, such as carvedilol, metoprolol, bisoprolol, and nebivolol, may also be extrapolated to the ACHD population. In a large retrospective study of 4358 adults with CHD and a systemic LV, 12% had a left ventricular systolic dysfunction; the prevalence was higher in right-sided compared with left-sided lesions [3]. In this study, 56% received guideline-directed medical therapy, resulting in a 6% increase in left ventricle ejection fraction (LVEF).

HF with preserved ejection fraction (HFpEF) is less common in ACHD patients, but may be underdiagnosed [4]. Diuretics are used for symptom relief, β-blockers may help by prolonging ventricular filling. Recent large, randomized control trials have shown that sodium–glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in HFpEF [5,6]. This was an important finding, knowing up to now, the treatment of HFpEF has been characterized by lack of therapies that improve prognosis. SGLT2i are theoretically promising in ACHD with reduced and preserved LVEF but need further investigations.

The APPROPRIATE study (ACE inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation In Adults with repaired TEtralogy of Fallot) was a randomized double-blinded, placebo-controlled trial comparing ramipril 10 mg daily with placebo in 64 patients with repaired tetralogy of Fallot and at least moderate pulmonary regurgitation [7]. Post-hoc echocardiographic analysis revealed that six months of treatment appear to stabilize systolic and diastolic LV function.

Scarce data are available considering sub-pulmonary right ventricular (RV) HF. It can be the result of either pressure overload or volume overload. When present, residual anatomic lesions must be addressed by surgery or interventional approach.

In the case of pressure overload secondary to pulmonary arterial hypertension (PAH), ultimately Eisenmenger syndrome, medical therapy focuses on the pulmonary circulation with introduction of PAH-specific drugs, namely endothelin-receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogues [8] (see Section 3). Risk assessment is therefore recommended for all patients, and initial oral combination or sequential combination therapy must be proposed.

In the case of HF due to volume overload, mainly represented by patients with severe pulmonary regurgitation in repaired tetralogy of Fallot, diuretics can be used to relieve symptoms. In asymptomatic patients, no medications are indicated.

The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is a multicenter, prospective, randomized, double-blind, placebo-controlled study [9]. Ninety-five adults with repaired tetralogy of Fallot and mild RV dysfunction in the absence of severe valvular lesions, were enrolled. Forty-seven received 150 mg losartan daily and forty-eight received placebo. Patients were treated for 21 ± 4 months. Losartan did not significantly improve RV ejection fraction (RVEF) in comparison with placebo. It also did not improve peak aerobic exercise capacity. Favorable effects of losartan in symptomatic patients were not statistically significant. Losartan should not be prescribed routinely in these patients to prevent the progression of RV dysfunction and RVHF.

ACHD with a systemic right ventricle (sRV) cannot support cardiac output in the long run. Tricuspid regurgitation, impaired coronary flow reserve, myocardial fibrosis, and ventricular dyssynchrony are highly interconnected and contribute to sRV failure. Clinical HF is common in patients with sRV, and over time [10], the HF burden in patients with atrial switch repair and congenitally corrected transposition of the great arteries will only increase. Recent improvements in the management of HF may improve sRV failure management.

Beta blockers are considered as central in HF management, although results in sRV are conflicted. Bisoprolol and carvedilol, in small cohorts of patients, were safe and tended to improve RV/LV volumes and function [11,12,13]. RV dilatation has been related to increased epinephrine and norepinephrine levels, potentially explaining the efficacy of beta-blockers in this setting. However, careful monitoring is necessary, as beta-blockers can also lead to conduction disorders in transposition of the great arteries.

As cardiac fibrosis is a common pathway leading to myocardial dysfunction, aldosterone blockage could be useful as it is thought to prevent myocardial fibrosis [14]. Eplerenone, an aldosterone blocker, has been assessed in small cohorts of patients (27 patients in sum) [15,16] and failed to prove any significant effect on RV mass changes, exercise capacity, serologic markers of collagen turnover, and inflammation.

Angiotensin II receptor blockers (ARBs) such as valsartan significantly reduce morbi-mortality in HFREF [17]. Several studies attempted to assess the effect of ARBs in sRV. First, losartan has failed to improve exercise capacity or natriuretic peptides [18]. In a randomized trial, there was no significant effect of valsartan on RV ejection fraction, exercise capacity, or quality of life [19]. Ramipril, an angiotensin converting enzyme (ACE) inhibitor, in a small but prospective, randomized controlled clinical trial, has also failed to improve RV function in adult patients with sRV after Senning or Mustard procedure [20]. Thus, until today, there is no conclusive evidence regarding the beneficial effect of ACE inhibitors or ARBs in adult patients with systemic RVs. 

Angiotensin receptor–neprilysin inhibitors (ARNI) have emerged as a standard of therapy for adults with HF [23]. Conflicting data have been presented about ARNIs in ACHD patients. Data from case reports and prospective cohorts indicate improvements in NT-pro-BNP and sRV function [24,25,26,27]. Overall, ARNIs seem to be very well tolerated in patients with a sRV [25]. However, in a small retrospective cohort including 12 patients with a sRV [28], sacubitril/valsartan failed to improve sRV function and exercise capacity. More recently, sacubitril/valsartan has been well tolerated and associated with improved sRV function, clinical status, and exercise capacity in two larger cohorts of patients [26,27].

Finally, tadalafil, a phosphodiesterase-5 inhibitor, has been studied in the SERVE trial [29], but results have not yet been published.

The Fontan procedure is one of the great advances of CHD surgery that has been successful in treating patients with single ventricle physiology by eliminating cyanosis and chronic volume overload. The Fontan circulation creates a direct connection between the systemic veins and the pulmonary arteries, bypassing the heart and allowing for direct flow into the pulmonary arteries without the use of a ventricular pump. However, many patients who undergo Fontan-type operations experience complications, such as reduced exercise tolerance, leg edema, pleural effusions, ascites, liver disease, arrhythmia, and protein-losing enteropathy (PLE), which can negatively impact their quality of life and increase their mortality [30]. To optimize the Fontan circulation, it is crucial to maintain low pulmonary vasculature resistance (PVR) and preserve both the systolic and diastolic function of the single systemic ventricle. However, a “failing Fontan” circulation is an almost inevitable long-term consequence of the altered physiology apparent in an increasing number of patients, and despite efforts to correct structural lesions using interventional procedures, increased PVR and progressive single ventricle dysfunction remain important contributors to late circulatory failure [31].

For the past decade, pulmonary vascular disease has been suspected to be the primary mechanism for late Fontan failure. A study based on autopsies described a unique remodeling of the pulmonary arteries with intimal hyperplasia and media regression in patients with late failing Fontan, which has been attributed to long-term non-pulsatile low-shear flow of the Fontan circulation [32,33]. Consequently, most randomized control trials assessing drug effects in Fontan patients have targeted PVR with limited and controversial outcomes. A meta-analysis including nine studies examining therapy for pulmonary arterial hypertension in Fontan patients showed significant improvements in hemodynamics, functional class, and 6 min walk distance [34]. However, there were no changes observed in mortality or levels of N-terminal proB-type natriuretic peptide (NT-proBNP) [34]. Most of these studies had a short duration, small sample size, and mainly included stable and asymptomatic Fontan patients. Two randomized clinical trials have confirmed that vasodilators have a limited effect on Fontan patients. The TEMPO study, which involved 69 patients, reported an improvement in exercise capacity with the use of bosentan, resulting in a modest increase in exercise duration [35]. In the Fontan Udenafil Exercise Longitudinal (FUEL) multicenter trial involving treatment with udenafil in 400 asymptomatic Fontan patients, no improvements were observed in oxygen consumption at peak exercise, NT-ProBNP level, or myocardial performance index [36]. Finally, the Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study evaluating the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects (NCT03153137) trial, which compared the efficacy and safety of macitentan with a placebo in asymptomatic Fontan patients, was terminated prematurely due to a lack of significant clinical benefits (results are not yet published). None of these trials showed a decrease in late failing Fontan incidence. Two studies described PAH therapies used in failing Fontan. The first was a multicentric observational study that found functional class was more likely to improve in treated patients after a median of 12 months [37]. The second was an open label, non-controlled study that failed to show an overall significant improvement after 3 months of treatment with bosentan in 10 patients with a failing Fontan although saturations of oxygen and/or exercise capacity improved in half [38]. These controversial results may be explained by an inadequate choice of therapeutic target knowing that multiple mechanisms are at the origin of Fontan failure, and that the increase in PVR is involved in less than 20% of Fontan failures [31]. Consequently, European guidelines recommend considering pulmonary arterial hypertension therapy in selected Fontan patients with elevated pulmonary resistance (PVR > 2 indexed Wood units) in the absence of high ventricular end diastolic pressure [39].

A recent study with longitudinal hemodynamic monitoring demonstrated that systolic (46%) but also diastolic (31%) single ventricle dysfunction were the most prevalent etiologies of late Fontan circulation failure [31]. The systemic single ventricle is subjected to a series of stresses, ranging from extreme volume overload to decreased preload after Fontan completion. These stresses can lead to the development of eccentric hypertrophy, dilation, as well as systolic and diastolic dysfunction. Despite this, there is currently no standardized management plan for treating or preventing systolic and diastolic dysfunction in Fontan patients. Furthermore, there is no evidence that HF therapy, which is commonly used for patients with acquired heart disease, can effectively alleviate symptoms or improve the prognosis of Fontan patients, notably when the Fontan circulation is failing. In one randomized study of angiotensin-converting enzyme inhibitors (enalapril) in Fontan patients without congestive HF, the active treatment group showed lower cardiac index during exercise [40]. Preload deprivation represents the Achilles’ heel of Fontan physiology and can result from such treatments in asymptomatic patients. A recent crossover trial found that carvedilol did not improve exercise performance and was associated with a mildly increased N-terminal-proBNP level [41]. Finally, it is unknown whether the significant benefits of sacubitril/valsartan and SGLT2i in HF in the absence of CHD would have a similar impact on diuresis and prevention of adverse cardiac remodeling in patients with failing Fontan.