Atrial arrhythmia is the most common complication in the adult congenital heart disease population, and with an aging population, atrial fibrillation is rapidly increasing in prevalence—particularly in those with concomitant heart failure. There is much to be determined regarding the pathophysiology of atrial fibrillation in the adult congenital heart disease population, but it is likely linked to the congenital heart defects, shunts, surgical patches, and coexisting hemodynamic lesions associated with the congenital heart disease process and physiology. This review focuses on the management of atrial fibrillation and heart failure in patients with adult congenital heart disease.
Key points
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Atrial arrhythmia and heart failure (HF) represent both the most common and clinically important sources of morbidity and mortality among adults with congenital heart disease.
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The optimal management strategy of atrial fibrillation (AF) and HF will be dependent on the morphology of the failing ventricle.
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Limited data exist regarding the efficacy of antiarrhythmic drugs in adults with congenital heart disease.
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The growing literature on AF ablation supports feasibility and safety, albeit with modest results.
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A greater appreciation of underlying AF mechanisms and substrates may contribute substantially to further improving outcomes in adults with adult congenital heart disease and AF.
Introduction
Atrial arrhythmia and heart failure (HF) represent both the most common and clinically important sources of morbidity and mortality among adults with congenital heart disease (adult congenital heart disease [ACHD]). With advances in management, the number of patients with ACHD has increased from 1.4 million to 2.2 million over the past decade, and this number continues to grow. However, with a decline in early mortality, there has been an accumulation of chronic complications in this population. In fact, in patients with ACHD, it is estimated up to 40% will develop HF and over 50% will develop atrial arrhythmia with the 2 often coexisting. Multiple factors can lead to atrial fibrillation (AF) and HF including hypoxemia, residual shunts, valvular dysfunction, surgical conduits, pulmonary hypertension, ischemia, and electromechanical dyssynchrony. In addition to shared risk factors, AF itself can cause HF and vice versa. The bidirectional interactions between AF and HF have become increasingly important in the management of patients with ACHD as the existence of one or both entities reaches near ubiquitous levels in this aging population. The role of multidisciplinary team management in these patients has become increasingly important to achieve good clinical outcomes.
This review focuses on the management of AF and HF in patients with ACHD. This has been broken into management of AF in 4 failing morphologic ventricular anatomies in ACHD ( Table 1 ). Attention will focus on the pathophysiology of AF in each type, drug therapy, catheter ablation, and surgical ablation options while highlighting the pathophysiological overlap.
| Failing Ventricular Morphology | Etiology of ACHD | Pathophysiology of AF | Mean Age of AF Onset | Prevalence of AF | Mortality Risk | AF Recurrence Class III Drug Therapy | AF Recurrence Post-CA |
|---|---|---|---|---|---|---|---|
| Systemic LV | Coarctation of the aorta |
| 40 , | 8%–15% , | HR 1.06 | 45% | 68% |
| Congenital AS | 53 | 19%–40% , | Limited data | Limited data | Limited data | ||
| Left-sided valvular regurgitation | 53 | 16%–36% | HR 1.28 | 90% , | 52%–74% , | ||
| Shone syndrome | 35 | 29% | HR 1.2 | Limited data | 80% | ||
| Subpulmonic RV | Ebstein anomaly |
| 42 | 8%–50% | HR 1.82 | Limited data | 3 case reports , |
| Pulmonary stenosis | 48 | 4% | No published data | Limited data | No published data | ||
| ToF | 44 | 7%–30% | HR 1.94 | 31% | 94% acute success | ||
| Systemic RV | CCTGA |
| 46 | 14%–49% | HR 3.5 | Limited data | 55%–80% |
| d-TGA |
| 35 | 19%–45% | HR 3.5 | Limited data | 46%–58% , | |
| Single ventricle | AP Fontan |
| 29 | 38%–40% , | HR 3.0 | 23.8% (55.7% experience SEs) | 29% |
| LT Fontan | |||||||
| EC Fontan |
Atrial fibrillation in congenital heart disease
The incidence and prevalence of AF in ACHD has increased exponentially over time as this group of patients are growing older due to great strides in surgical techniques and medical care during the last decades. In fact, atrial arrhythmias are the most common complication encountered in the growing and aging population with ACHD. The annual incidence of AF in ACHD is estimated at 7.6 in 1000 per year, which is considerably higher than the general population at 1.4 in 1000 per year. Although intra-atrial re-entrant tachycardia (IART) is the prevailing atrial arrhythmia, the number of patients with ACHD and AF has increased linearly with improved survival and aging of the population ( Fig. 1 ).
The demographics and etiology of AF in patients with ACHD differ significantly from the general population. Furthermore, AF progresses more rapidly in the ACHD population from paroxysmal, persistent to permanent compared to the general population. It is estimated that paroxysmal or persistent AF will progress to permanent within 3 years of first diagnosis in patients with ACHD. Certain conditions are associated with a greater risk of AF in particular right-sided lesions including secundum atrial septal defects (ASD), atrioventricular (AV) septal defects, Ebstein anomaly of the tricuspid valve (TV), tetralogy of Fallot (ToF), and tricuspid atresia.
The fundamental electrophysiological mechanism of AF relies on a specific trigger, which is then maintained by the presence of an underlying arrhythmogenic substrate. Focal electrical activity provoked by micro-re-entry or triggered activity is the basis for AF genesis. The primary source of this triggered activity is the pulmonary veins (PVs) of the left atrium in the general population. However, in ACHD, as perhaps anticipated, the prevalence of non-PV triggers is much higher. One study of 660 patients observed non-PV triggers more commonly in patients with nonparoxysmal AF, right atrial (RA) enlargement and biatrial enlargement compared to those with PV triggers. Non-PV triggers have been observed from the superior vena cava, crista terminalis, interatrial septum, coronary sinus ostium, left atrial (LA) roof/posterior wall and ligament of Marshall. , , However, non-PV triggers in both ACHD and the normal heart have not been fully elucidated, and further research is required to identify those substrates and localize trigger sources.
AF progression occurs as a result of (1) electrical, (2) structural, and (3) contractile remodeling. Electrical remodeling occurs rapidly and is characterized by shortened atrial refractoriness and loss of normal rate adaptation, which promotes AF occurrence. Contractile remodeling develops more insidiously and appears to arise from altered calcium transport and uptake and subsequent depression of the L-type calcium current. Structural changes develop over a longer period and are characterized by diffuse scarring and chamber enlargement. The consequences of AF remodeling in ACHD includes (1) structural changes leading to arrhythmogenic cardiomyopathy and atrial enlargement leading to valvular regurgitation and HF, (2) contractile remodeling leading to hypotension caused by loss of atrial systole and irregular ventricular contractions, and (3) electrophysiological remodeling leading to sinus node dysfunction and promoting AF recurrence. Structural and contractile remodeling can lead to thromboembolic consequences such as ischemic strokes and microemboli causing reduced cognitive function. These observations with durable AF imply that aggressive upfront restoration of sinus rhythm may improve outcomes. Rhythm control is generally preferable as the initial strategy to prevent major hemodynamic consequences. Multiple studies have shown a positive impact of a rhythm control strategy in the general population with a significant increase in catheter ablation as a first-line strategy. , , Furthermore, CASTLE-AF and CASTLE-HTx both observed a significant mortality benefit of AF catheter ablation in patients with HF in the general population. , These data cannot be extrapolated to the ACHD community due to differences in success rates of ablation, and due to nonreversible remodeling in complex congenital heart disease.
Heart failure in congenital heart disease
HF is the leading cause of death in ACHD. Many simple lesions such as ASD or patent ductus arteriosus can be repaired in childhood without significant increased risk of HF. However, for patients with complex congenital heart disease such as the single ventricle physiology, ToF, and transposition of the great arteries (TGA), the development of HF is common often requiring advanced management with mechanical circulatory support (MCS) and/or heart transplantation (HT). The failing ventricle in the population with ACHD can be divided into 4 archetypal ventricular morphologies: (1) systemic left ventricle (LV) , (2) subpulmonary right ventricle (RV) , (3) systemic RV, and (4) single ventricle. There are many potential causes of HF in ACHD including valvular dysfunction, shunts, arrhythmias, venous obstruction, and systolic and/or diastolic dysfunction that require evaluation and treatment.
The variability can make the diagnosis of HF in this population challenging as their anatomy and physiology defy standard measurements of myocardial function. This represents a significant challenge as by the time HF is established the underlying myocardial and electrophysiological maladaptive processes may have been present for decades in the setting of diminished circulatory reserve. An important difference between patients with ACHD and the general population is the threshold for ejection fraction less than 40%, which depending on the morphology of the systemic ventricle may not be applicable. , Two patient subsets that pose particular challenges for diagnosis are the symptomatic patients with normal systemic ventricular function and the asymptomatic patients with impaired function of the systemic RV. In these 2 constellations, the European guidelines suggest a decrease of peak oxygen consumption by 25% in cardiopulmonary exercise testing (CPET) or 2 fold increase of N-terminal pro-B-type natriuretic peptide (NT-proBNP) during 6 months of follow-up are indicators to start treatment. Drug therapy, device implantation, and MCS are variable and tailored to the morphology of the failing ventricle. In general, patients with ACHD with a systemic LV are treated in a similar manner to the general population. In terms of mechanical support, in the largest study to date, more patients with ACHD require biventricular assist implantation or total artificial heart than the general population, and they more commonly have concomitant dysfunction of the subpulmonic ventricle and pulmonary hypertension. In terms of HT, patients with ACHD frequently have concomitant pulmonary hypertension or extracardiac involvement such as liver disease, which can limit transplant candidacy. , Therefore, early diagnosis and management of HF is vital to improve clinical HF outcomes in the ACHD population.
Atrial arrhythmias including AF represent a potential reversible cause for HF in patients with ACHD. Prompt diagnosis, treatment, and maintenance of sinus rhythm could prevent the electrical and structural remodeling that leads to ventricular dysfunction and HF. Equally, the management of AF in patients with established HF is of paramount importance to prevent worsening ventricular function and ultimately reduce mortality in this population. However, the optimal management strategy of AF and HF will be dependent on the morphology of the failing ventricle.
The failing systemic left ventricle
Pathophysiology
Systolic dysfunction of the morphologic systemic LV is defined by the ACC/ESC as an ejection fraction less than 40%, which in this scenario is applicable to ACHD. This can occur secondary to pressure overload (coarctation of the aorta and congenital aortic stenosis), volume overload (left-sided valvular regurgitation and large ventricular septal defects), coronary artery disease (both congenital and acquired as a complication of a Ross or arterial switch procedure), restrictive physiology (Shone syndrome), and RV failure. Failure of the systemic LV causes neurohormonal and sympathetic nervous system activation, which ultimately leads to fibrosis and electrical remodeling including shortening atrial refractoriness that promotes AF recurrence. Treatment of AF in this cohort can be challenging as certain drugs that suppress atrial arrhythmias can be proarrhythmic in a scarred or failing ventricle.
Drug Therapy
Treatment of systemic LV failure in ACHD should follow conventional guidelines for LV dysfunction. guideline directed medial therapy (GDMT) for HF known as the 4 pillars in the form of (1) beta blockers; (2) angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors; (3) mineralocorticoid receptor antagonists; and (4) sodium-glucose cotransporter-2 inhibitors are the mainstay of HF treatment. , Therefore, rate control in this group is primarily in the form of selective beta blockers (bisoprolol and metoprolol) and nonselective beta blockers (carvedilol). Carvedilol has the best evidence base for LV reverse remodeling; however, beta-1 selective agents have greater antiarrhythmic effect in the form of reduced sarcoplasmic reticulum Ca 2+ load, which may reduce after depolarizations and triggered activity. Digoxin can be used as an alternative rate control agent in drug refractory cases or when beta blockers are poorly tolerated.
In terms of pharmacologic rhythm control agents, class Ic agents such as flecainide are contraindicated in patients with moderately impaired LV systolic dysfunction and coronary artery disease. Class III agents such as amiodarone and dofetilide are the most effective agents although neither has shown a mortality benefit in HF in a non-ACHD population. Furthermore, amiodarone is associated with significant end-organ toxicity such as thyrotoxicosis, pulmonary fibrosis, and hepatotoxicity, which limits its use in the longer term and may impact on advanced HF therapies if required. Other agents such as dronedarone and sotalol are not recommended in patients with reduced LV systolic function and clinical evidence of HF. ,
Catheter Ablation and Surgical Intervention
In patients with symptomatic AF refractory to drug therapy and/or HF with reduced LV systolic function, catheter ablation carries a class I indication. , More recent guidelines recommend catheter ablation as a first-line therapy in patients with paroxysmal AF. Among ACHD patients with persistent AF and HF, catheter ablation remains a reasonable first-line therapy in experienced high-volume centers. Targets for ablation in ACHD patients with systemic LVs are similar to the non-ACHD population and pulmonary vein isolation (PVI), LA posterior wall isolation, and cavotricuspid isthmus (CTI) lesion sets are extrapolated from patients without ACHD. Preprocedure computed tomography (CT)/MRI is recommended to assess anatomic variation, assess LA size, and potentially identify substrate via contrast agent enhancement. Much of the reported experience with catheter ablation utilized radiofrequency ablation (RFA). , Less evidence is available for the use of cryoablation; however, initial experience has shown it is safe with similar efficacy to RFA. Pulsed field ablation (PFA) is a nonthermal energy source approved for catheter ablation of paroxysmal AF with promising results in the general population; however, there is only 1 report of 21 patients with various types of ACHD showing PFA is safe with similar efficacy to conventional RFA. CASTLE-AF observed a significant mortality benefit associated with AF catheter ablation in the HF population, which was expanded in CASTLE-HTx demonstrating a reduction in a composite outcome of all-cause mortality, LV assist device implantation and urgent HT with AF catheter ablation. , Given the mortality benefit of catheter ablation established in these trials, the prevalence of AF and significant mortality rate associated with HF in ACHD, it could be argued that AF catheter ablation could be the fifth pillar of HF management for ACHD patients with a failing systemic LV.
Most atrial arrhythmia in ACHD with a systemic LV can be managed by catheter ablation, but certain cases can be refractory usually due to excessive atrial wall thickness limiting transmural lesion formation and facilitating epicardial breakthrough. In such cases where appropriate, surgical ablation can be considered at the time of other surgical interventions. A recent study suggests that intraoperative use of cryoablation in AF or IART can also be feasible and safe, having no intraoperative complications and promising midterm results.
The failing subpulmonic right ventricle
Pathophysiology
There are limited data available on the management of both AF and HF in patients with a failing subpulmonic RV. The most common cause is pressure overload (pulmonary stenosis, ToF, or Eisenmenger syndrome) and volume overload (chronic left-to-right pretricuspid shunts, right-sided valvular regurgitation such as Ebstein anomaly). In ToF, initially, the RV becomes pressure overloaded and hypertrophied in response to pulmonary stenosis. Therefore, late surgical repair is one of the risk factors for RV dysfunction. After surgical repair, patients are often left with pulmonary regurgitation, which can cause RV volume overload and dilatation overtime. Pulmonary valve replacement may halt progression of RV failure; however, it has not been shown to reduce arrhythmia burden. Previous studies have shown atrial arrhythmia in up to 43% of patients with ToF, most commonly macro-re-entrant arrhythmias with an increasing prevalence of AF in the fourth decade of life. , It is likely that progressive hemodynamic sequelae such as RV pressure or volume overload induce atrial and ventricular remodeling, which affect conduction and can predispose patients with higher risk anatomic substrate to develop clinical arrhythmias.
Drug Therapy
There is a paucity of data on antiarrhythmic therapy in the failing subpulmonic RV. In general, catheter ablation is more effective than antiarrhythmic therapy for the treatment of atrial flutter and IART, which is more common in this group. Limited data suggest that rhythm control with antiarrhythmic drugs in patients with ToF is ineffective for the prevention of AF progression. , For patients with Ebstein anomaly and HF, nondihydropyridine calcium channel antagonists and digoxin should be used with caution given the prevalence of accessory pathways in Ebstein anomaly. Beta blockers are ineffective in controlling the rate in pre-excited AF while digoxin and nondihydropyridine calcium channel antagonists have been shown to shorten the effective refractory period of accessory pathways. Class III agents may help to control arrhythmia burden but guideline consensus favors catheter ablation in these patients due to the side effects associated with long-term amiodarone therapy.
Catheter Ablation and Surgical Intervention
Catheter ablation of AF in patients with a failing subpulmonary RV is a reasonable therapeutic strategy for both drug-refractory cases and as a first-line therapy. Non-PV triggers are common owing to RA myopathy secondary to long-standing maladaptive RV physiology. IARTs are far more common in this group, which is known to precede, trigger, or coincide with AF; therefore, the RA substrate should be targeted with an attempted AF ablation. Not only are typical re-entrant substrates observed but also multiple circuits within the RA free wall can hinder attempts at catheter mapping and ablation. In some situations (eg, Ebstein anomaly after cone repair), substrates may be difficult to approach conventionally, where plication of atrialized ventricle and/or implantation of a bioprosthetic valve can cover culprit atrial myocardium.
Surgical intervention on the TV is often required for patients with ACHD, which can have significant implications regarding catheter ablation of AF in the failing subpulmonic RV. Conceptually, after TV ring annuloplasty or replacement, a portion of the CTI may become covered by bioprosthetic material preventing complete linear ablation of the isthmus. The largest multicenter study to date on catheter ablation in patients with ACHD after TV surgery showed significantly lower acute success rates in TV ring/replacement in patients with ACHD compared to those with TV repair or no TV surgery. TV ring/replacement was a significant predictor of atrial arrhythmia recurrence at a median follow-up of 3 years. Given these considerations, patients expected to undergo TV replacement or annuloplasty ring could be considered for preoperative electrophysiology study for the evaluation and treatment of existing tachycardia substrates near the TV annulus.
In patients with Ebstein anomaly, atrial arrhythmia is common with up to 20% of patients observed to have one or multiple accessory pathways typically right-sided ( Fig. 2 ). Although the success rate of catheter ablation of accessory pathways is lower in patients with Ebstein compared to the general population it is the most favorable treatment strategy. In those patients who develop AF, the ACC/AHA recommends a biatrial MAZE procedure to treat AF in those that require corrective surgery due to hemodynamic instability.
