Curr Treat Options Cardio Med (2015) 17:5 DOI 10.1007/s11936-015-0376-z

Heart Failure (W Tang, Section Editor)

Managing Heart Failure in Adults with Congenital Heart Disease Thomas D. Ryan, MD, PhD, FACC John L. Jefferies, MD, MPH, FACC, FAHA Ivan Wilmot, MD* Address * The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 2003, Cincinnati, OH 45229, USA Email: [email protected]

* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Heart Failure Keywords Heart failure I Adult congenital heart disease I Management I Arrhythmia I Mechanical circulatory support I Ventricular assist device I Heart transplant Abbreviations ADHF Acute decompensated heart failure I ASD Atrial septal defect I ASO Arterial switch operation I D-TGA D-transposition of the great arteries I EF Ejection fraction I HF Heart failure I HLHS Hypoplastic left heart syndrome I ICD Implantable cardioverter defibrillator I LVEF Left ventricular ejection fraction I MCS Mechanical circulatory support I PDA Patent ductus arteriosus I RVEF Right ventricular ejection fraction I TAH Total artificial heart I TOF Tetralogy of Fallot I VAD Ventricular assist device

Opinion statement The current era of cardiology has seen a significant increase in the number of adults living with congenital heart disease (CHD). Although advances in medical and surgical management have resulted in approximately 90 % of children with CHD living into adulthood, many suffer from late complications, with myocardial dysfunction as the leading cause of morbidity and mortality. The heterogeneity of the adult congenital heart disease (ACHD) population has presented a challenge, as there are only limited data regarding appropriate treatment modalities. Given the growing ACHD population and the high morbidity and mortality related to myocardial dysfunction, a comprehensive approach to heart failure (HF) care is recommended in conjunction with ACHD and HF specialty care. The field must focus on developing research strategies to leverage existing and future medical and surgical treatment options in order to improve outcomes in this diverse population.


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Introduction Since the first report of successful surgical repair of a patent ductus arteriosus (PDA) by Gross in 1939, the groundbreaking work of Alfred Blalock, Vivien Thomas, and Helen Taussig in employing a shunt to circumvent pulmonary stenosis in 1945, and the first use of the heart–lung machine in the repair of an atrial septal defect (ASD) by Gibbon in 1954, advances in medical and surgical therapies have yielded dramatic improvements in reduced morbidity and mortality for patients with CHD [1–3]. Because of these successes, there is now a generation of adult patients encountering previously unknown complications. One example is ACHD patients who go on to develop endstage HF. There are currently more than 1 million patients with ACHD in the U.S., including “a substantial number of young adults with single ventricle physiology, systemic right ventricles, or complex intracardiac baffles” [4, 5].While the problem of the aging CHD patient has been appreciated for over 40 years, hospital admissions have doubled in recent years, with HF as the reason for admission in 20 % of ACHD cases [6, 7•, 8•]. The risk of death during hospital admission increases for patients with ACHD and HF compared to those with ACHD alone, and HF is the leading cause of death [8•, 9]. Treatment strategies for the ACHD patient with HF cannot simply mimic those for other causes of HF, such as ischemic heart disease, as the rationale for applying these guidelines is not clear in these settings, where the disease mechanisms can be quite divergent [10]. For instance, a failing morphologic right ventricle (RV) functioning as the systemic ventricle cannot be assumed to have the same mechanism of dysfunction as that of a

post-infarction left ventricle (LV). There is a wide variety of etiologies for HF in ACHD, including ventricular overload (volume or pressure), myocardial injury during prior procedures, residual defects, altered anatomy, neurohormonal activation, and associated comorbidities [11•]. The diagnoses most often associated with development of HF include tetralogy of Fallot (TOF), single ventricle physiology, and post-Mustard operation for transposition of the great arteries (TGA). Dysfunction is less common in left-to-right shunts, valvular disease, and coarctation of the aorta [12]. When assessing the degree of HF in the patient with ACHD, use of the American Heart Association/American College of Cardiology staging for heart failure may be more appropriate than standard classification. Under this scheme, patients are considered as follows: high risk to develop heart failure (stage A), structural changes but no clinical evidence for heart failure (stage B), structural disease with prior or current symptoms of heart failure (stage C), and refractory heart failure requiring specialized intervention (stage D) [13]. Guidelines for medical and surgical care of these patients recommend coordination by regional centers of excellence, including input from cardiologists and surgeons with significant expertise in the care of ACHD. Guidelines also specify that all high-risk patients, including those with HF, receive care at such centers when reasonably possible [14••]. The goal of HF therapy in ACHD is similar to that in patients without ACHD: reversal of pathologic remodeling, restoration of adequate systemic/pulmonary output, and improvement/resolution of symptoms.

ACHD: a heterogeneous population An understanding of the heterogeneity of ACHD is critical for determining future management strategies. Improved patient outcomes have shifted the population of patients palliated with Mustard/Senning operations to a larger number of Fontan patients, including those with hypoplastic left heart syndrome (HLHS), in the current era. Following initial palliative surgery for CHD in infancy or early childhood, many adults continue to have anatomic and hemodynamic abnormalities predisposing them to HF later in life. The mechanisms contributing to HF in the ACHD population are unique and differ from other forms of HF. The etiologies of ACHD may be divided into four categories: TOF, single ventricle physiology, complex intracardiac baffles, and systemic RV (Table 1). Patients with TOF often undergo palliative surgery in infancy to relieve RV

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outflow tract obstruction and resolve intracardiac shunting, only to exchange this for future chronic volume and pressure loading of the RV related to pulmonary insufficiency and stenosis, respectively. RV pressure and volume loading can lead to poor ventricular interactions, with reports that 20 % of patients who develop left ventricular systolic dysfunction experience a higher arrhythmia burden and worse outcomes [15, 16]. Single ventricle physiology is seen in patients born with HLHS. The staged palliative surgical approach involving initial Norwood/Sano, bidirectional Glenn (BDG), and ultimately Fontan in this population places them at high risk for future HF related to chronic venous congestion and/or ventricular dysfunction. Fontan patients also have high afterload, stroke work, and adverse ventricular-arterial coupling, and are at increased risk for ventricular remodeling and dysfunction [17]. Such patients are more likely to develop multiorgan-system disease, including cardiorenal syndrome and hepatopulmonary syndrome. As Fontan patients age, they may develop hepatic dysfunction, which can lower systemic vascular resistance. Patients with single ventricle physiology may also have associated genetic syndromes and anomalies, which have been noted as an independent risk factor for poor neurocognitive development [18]. In the past, patients with D-TGA or congenitally corrected TGA (CC-TGA) have undergone palliative surgery involving the creation of complex intracardiac baffles. In D-TGA, the stroke volume may be limited by a stiff atrial baffle and sinus node dysfunction. Additionally, this population is at high risk of developing HF related to venous obstruction and arrhythmias. In a comparison of long-term outcomes for ACHD patients with systemic RVs who underwent an atrial switch (Mustard/ Senning) versus arterial switch operation (ASO), a significant improvement in cardiac function, cardiorespiratory performance, and neurohormonal activity can be seen in the ASO group [19]. As such, more recently, patients with a systemic RV related to D-TGA have undergone ASO procedures (Table 1). Patients with D-TGA who undergo ASO are at risk of developing ventricular

Table 1. Adult Congenital Heart Disease Etiology and Surgical/Catheterization Interventions ACHD Etiology

Surgical Intervention

Catheter Intervention

Tetralogy of Fallot (TOF)

Transannular pulmonary valve patch

Melody® valve placement in RVOT conduita

Single ventricle physiology (e.g. HLHS) Complex intracardiac baffles (e.g., Mustard/Senning in D-TGA)

Staged palliation: Norwood/ Sano→BDG→Fontanb Consider baffle takedown, arterial switch, ± MAZE procedure following ventricular conditioningc Arterial switch (D-TGA) Consider atrial and arterial switch (CC-TGA)

Systemic right ventricle (e.g., D-TGA, CC-TGA) a

Percutaneous Melody® valve placement to treat dysfunction of prosthetic conduits inserted in the right ventricular outflow tract (RVOT) Fontan revision to an extracardiac conduit may be offered to patients with classic or intracardiac conduit type Fontan with associated heart failure c Mustard/Senning baffle takedown may be considered in patients with heart failure and related arrhythmias following future systemic ventricle conditioning with a banding procedure b


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Curr Treat Options Cardio Med (2015) 17:5 dysfunction, coronary artery disease, and aortic dilation. In contrast, those with CC-TGA are at risk for developing ventricular dysfunction, primary systemic atrioventricular valve regurgitation, and progressive atrioventricular block.

Managing adults with congenital disease: assessment and treatment of traditional cardiovascular risk factors As the number of patients with ACHD continues to increase, consideration must be given to the impact of traditional adult cardiovascular risk factors and risk of acquired heart disease. There are factors related to ACHD, including congenital coronary artery anomalies, coronary manipulation at time of surgery, and mechanical compression from conduits or dilated pulmonary arteries, that may inherently predispose patients to coronary artery disease [20]. Traditional risk factors have been assessed in ACHD and are present in a significant number of patients [21•]. The prevalence of systemic arterial hypertension has been reported as high as 50 % of the ACHD population, with potentially higher risk in specific populations such as patients with coarctation of the aorta [22•, 23]. Up to 40 % of ACHD patients may be overweight or obese, possibly as a result of previous advice promoting a sedentary lifestyle [24]. Dyslipidemia may be seen in up to 75 % of ACHD patients with known coronary artery disease, and may be of particular importance in the cyanotic congenital heart disease population [25]. Smoking is a well-established traditional risk factor, although the proportion of ACHD patients who smoke currently appears to be less than that of the general population. The prevalence of diabetes mellitus in patients with ACHD is around 3 %, which mirrors that of the non-ACHD population. Screening should be performed for patients with ACHD, with the goal of early detection. Treatment should be considered for identified cardiovascular risk factors, with lifestyle modification one of the first interventions. Appropriate medical treatment should also be considered, but care must be taken in choosing the type of therapy, given the potential for complex anatomy and variable response to treatment.

Medical therapies Although traditional HF therapies have been extensively evaluated in the nonCHD HF population, studies in the ACHD population are limited [26, 27]. These patients have reported functional impairment, neurohormonal activation, and adverse cardiac remodeling, suggesting that medications such as beta blockers or ACE inhibitors may be useful. However, as previously discussed, HF in patients with ACHD is less likely to be caused by LV systolic dysfunction, and more likely related to RV dysfunction, tricuspid regurgitation, pulmonary hypertension, or diastolic dysfunction, where such medications have not proven effective [11•]. A randomized placebo-controlled trial of bisoprolol failed to show improvement in peak oxygen consumption or RV ejection fraction (EF) in 33 patients with New York Heart Association functional class I or II status who had undergone surgical repair of TOF [26]. A similar study comparing ramipril

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versus placebo in patients with repaired TOF failed to show improvement in RVEF using magnetic resonance imaging [27]. These studies were limited to a six-month follow-up period, and outcomes were focused on RVEF, which may not have a predictable or consistent response to HF medical therapy. Small trials in TOF patients with LV systolic dysfunction failed to show improvement in EF with therapy using beta blockers or ACE inhibitors [26, 27]. These findings may be related to LV dysfunction secondary to ventricular interactions in patients with repaired TOF, and are supported by the improvement in the LVEF following pulmonary valve replacement [28]. Patients with single ventricle physiology palliated with the Fontan operation are at risk for ventricular dysfunction and venous congestion, which may benefit from afterload reduction and diuretic therapy, respectively. Additionally, patients who undergo a Fontan procedure are at risk of developing hepatic dysfunction, hepatopulmonary syndrome, and decreased systemic vascular resistance, suggesting that afterload reduction should be used with caution in such patients. Several studies have suggested that pulmonary vasodilator therapies such as sildenafil, which have been shown to improve ventilatory efficiency and anaerobic thresholds in some Fontan patients, may provide benefit in this population [29]. Several small case series have evaluated the effectiveness of beta blockers in patients with systemic RV, with some evidence of improvement in ventricular size and function [17]. The effectiveness of inhibition of the renin-angiotensin-aldosterone system in patients with systemic RV is limited to small studies. In a multicenter doubleblind randomized controlled trial comparing valsartan to placebo in patients with systemic RV, there was no significant effect of valsartan on RVEF, exercise capacity, or quality of life at three-year follow-up [30]. Arrhythmias are common in the ACHD population, especially in patients with HF. The lifetime cumulative risk of arrhythmia is greater than 50 % for patients born with CHD, and arrhythmias complicate at least half of all HF admissions among patients with CHD [31]. A comprehensive evaluation of medical, catheter-based, and surgical options for atrial and ventricular arrhythmia is needed for management of HF in these patients. Prior surgical interventions place them at increased risk of developing arrhythmia. Sinus node dysfunction is common in patients who have undergone atrial baffle procedures (Mustard or Senning) for D-TGA. Atrioventricular conduction defects occur frequently following ventricular septal defect repair or aortic valve surgery and during Konno enlargement of a hypoplastic left ventricular outflow tract. Surgical scar regions such as around the atrial baffle can lead to macro-reentrant tachyarrhythmias. Atrial reentrant arrhythmias are often scar-based, and the cycle length is usually long (300–500 ms). This can result in 1:1 atrioventricular conduction, and has been linked to sudden cardiac death in patients with DTGA, where beta blockers may be protective [32]. In patients with single ventricle anatomy who have undergone Fontan palliation, intra-atrial reentrant tachycardia may occur at a ventricular rate of 100 beats per minute, related to a cycle length of 300 ms, and 2:1 conduction. This is slower than the typical isthmus-dependent atrial flutter with a ventricular rate of 150 beats per minute, making detection of this arrhythmia difficult. Stagnant flow in the Fontan circuit is common, and anticoagulation is indicated for thromboprophylaxis in Fontan patients with atrial arrhythmias [11•, 14••]. Although antiarrhythmic medications are often ineffective in controlling atrial arrhythmias, and can exacerbate sinus node dysfunction that is common in Fontan patients,


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Curr Treat Options Cardio Med (2015) 17:5 radiofrequency ablation has been used successfully. However, although radiofrequency ablation has a high acute procedural success rate, most patients have multiple reentrant circuits and high rates of recurrence, up to 40 % at two years [33]. Early identification of atrial arrhythmias, assessment of hemodynamic perturbations, and prompt intervention, when possible, is recommended [11•]. Surgical therapy with Fontan revision with a Cox-Maze procedure tailored to the Fontan anatomy should be considered [34]. Although patients with chronic systolic HF and a wide QRS have been shown to benefit from cardiac resynchronization therapy (CRT), the role of CRT in patients with ACHD and HF is less well defined. Retrospective studies evaluating CRT in a heterogeneous CHD population found epicardial placement present in up to 50 % and improvement in EF or functional class in 3287 % of patients [35–37]. Although CRT resulted in improvement in this heterogeneous population, recommendations for specific CHD lesions could not be extrapolated from these studies. Small studies utilizing CRT in patients with systemic RVs have shown a possible benefit. A single multicenter study reported an average 13 % improvement in EF in 13 of 17 patients with systemic RVs treated with CRT [36]. Implantable cardioverter defibrillator (ICD) criteria are well established in patients with acquired HF, and indicated as secondary prevention in patients who have survived cardiac arrest or who have experienced sustained symptomatic ventricular tachycardia [14••]. There is significant controversy surrounding primary ICD implantation in the CHD population. ACHD patients may require epicardial lead placement of a CRT or ICD system at a young age, resulting in increased surgical morbidity with future lead replacements and generator changes. Several studies have also found high rates of inappropriate shocks (24-41 %) that may be related to supraventricular arrhythmias in the younger population [31, 38–40]. Medical therapies should be tailored to each ACHD patient. Traditional HF medical therapies are often not applicable in this population in light of the characteristic disease heterogeneity, unusual mechanisms of HF, and unique comorbidities of HF in patients with ACHD. Arrhythmias are common, and should be identified early, corrected if possible, and evaluated for possible benefit of CRT and/or ICD.

Surgical and percutaneous strategies When medical therapies have been exhausted, a patient with HF in the setting of ACHD may benefit from percutaneous, surgical, or advanced mechanical circulatory support (MCS) strategies. In these patients, consideration must be given to the unique anatomy and physiology present, including residual lesions, shunting, and inherent myocardial or conduction system disease. Percutaneous interventions and devices offer a minimally invasive route for addressing congenital defects that can lead to pressure or volume overload of the ventricles. Lesions amenable to percutaneous palliation can generally be categorized as: 1) shunting lesions leading to volume overload of various chambers (ASD, ventricular septal defect, PDA), 2) “right-sided” obstructive and regurgitant lesions that cause pressure and/or volume overload on the pulmonary ventricle (pulmonary valve or conduit stenosis and/or regurgitation), and 3) “left-sided” obstructive lesions producing pressure overload of the

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systemic ventricle (aortic valve stenosis, aortic coarctation) [37]. Some of the first percutaneous devices were developed over 40 years ago for closure of PDA and ASD [41, 42]. Since then, a variety of septal occluders and vascular coils/ plugs have become available for similar applications. These devices are also used in closing baffle leaks after arterial switch procedures, collateral vessels associated with single ventricle palliation, and surgically created fenestrations. Balloon valvuloplasty for pulmonary and aortic valve stenosis was first described in the early 1980s in isolated valvular disease, and similar applications were reported for coarctation of the aorta [43–45]. In the past decade, the field has evolved to encompass the capacity for balloon dilation of stenotic valves or conduits, or delivery of a prosthetic replacement valve via catheter (e.g., Melody valve, Medtronic) [46]. Recent applications have demonstrated the use of this technology in the tricuspid, mitral, and aortic positions as well as in single ventricle physiology [47••, 48••, 49]. A common application in ACHD has been to address stenotic and regurgitant RV outflow tracts in patients with repaired TOF. Surgical approaches in the ACHD patient with HF can be used to address the underlying problem when a percutaneous approach is inappropriate or unavailable. Similar to percutaneous interventions, closure of residual shunting lesions and baffle leaks or repair of regurgitant valves can decrease ventricular volume overload, while surgical repair of stenotic valves can relieve ventricular pressure overload. One particularly challenging issue in ACHD care that serves as an example of potential surgical intervention is the “failing Fontan”. First described in 1971 as total cavopulmonary anastomosis to palliate tricuspid atresia, the Fontan procedure and its many modifications have since offered palliation to a large number of patients with single ventricle defects [50]. The original atriopulmonary connection is susceptible to atrial dilation, arrhythmias, and baffle thrombus, among other problems [51]. Conversion of the Fontan to either a lateral tunnel or extracardiac conduit configuration has been proven a valid solution in appropriately selected patients [51]. Another group of patients at risk of developing HF are those with a systemic RV, particularly DTGA status post-atrial switch or unrepaired CC-TGA. Attempts have been made to convert to a late arterial switch, with pressure-banding of the LV to adapt to systemic pressure. Unfortunately, success has been limited, and this procedure has not been undertaken as a common solution [52]. The current practice of early ASO may address such issues, but long-term survivors for study are only now emerging. Overall, surgical procedures are carried out in 20 % of ACHD patients, with 40 % of these cases of reoperation. Patients undergoing subsequent surgeries are at increased risk for death compared to patients never operated on, necessitating careful consideration prior to embarking on this path [53]. MCS is an exciting area of growth within the realm of HF care, including in patients with ACHD, although reports of the latter are primarily anecdotal. With this approach, designed to support circulation in a two-ventricle system, challenges can arise when significant shunting, stenosis, or regurgitation is present. However, the use of several currently available devices has been reported in patients with ACHD [54]. Options for support can be categorized as either short-term (days to weeks) or mid- to long-term (months to years) (Table 2). Short-term devices are designed to function as a bridge to recovery or to a more definitive therapy, including transplantation. In general, they are placed


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Table 2. Mechanical circulatory support devices available in the Unites States; adapted from Mulukutla et al. [54] Device



Minimum Patient Size

Flow Rate (L/min)

Short-Term ECMO


Centrifugal or roller pump Centrifugal Centrifugal Centrifugal Centrifugal



None G20 kg 920 kg 91.3 m2

G10 G1.5 G10 G5


91.3 m2

G2.5; G5

Intra-aortic Extracorporeal

Counterpulsation Displacement

91.3 m2 91.3 m2

G1.5 G6

Extracorporeal Extracorporeal/ preperitoneal pocket Preperitoneal pocket Pericardial Preperitoneal pocket Left ventricle Orthotopic

Pulsatile Pulsatile

93 kg 90.7 m2

Variablea G7

Continuous Continuous Continuous Continuous Pulsatile

91.1 m2 91.2 m2 91.3 m2 91.2 m2 91.7 m2b

G8 G10 G10 G7 G9.5

ROTAFLOW (Maquet) PediMag (Thoratec) CentriMag (Thoratec) TandemHeart pVAD (CardiacAssist) Impella 2.5, 5.0 (Abiomed) IABP (Maquet) AB5000 (Abiomed) Mid- and Long-Term EXCOR (Berlin Heart) PVAD/IVAD (Thoratec)

DuraHeart (Terumo Heart) HeartWare HVAD (HeartWare) HeartMate II (Thoratec) Jarvik 2000 (Jarvik Heart) SynCardia TAH (SynCardia) a b

Extracorporeal Extracorporeal Extracorporeal Extracorporeal or atrial transseptal Trans-aortic valve

Dependent on pump size (available in 10, 25, 30, 50, 60 ml) Also requires 910 cm between sternum and 10th vertebral body measured by computed tomography

without the need for invasive surgery. This category includes extracorporeal membrane oxygenation and similar systems without the inline oxygenator, such as the centrifugal pumps ROTAFLOW (Maquet) and CentriMag (Thoratec). Also included are the Impella (Abiomed), a transaortic valve device placed by catheter, and the intra-aortic balloon pump inserted in the descending aorta via femoral arterial access. Mid- and long-term devices also function as a bridge to recovery or other therapy, but particular devices can alternatively be considered for destination therapy. Designed as a ventricular assist device (VAD) for the left ventricle, this option is represented by the HeartWare HVAD, Thoratec HeartMate II, and Jarvik 2000, among others (Table 2). A number of individual or paired case reports have been published, but the largest series to date documented implantation of a VAD in six ACHD patients. This series comprised the use of the HeartMate II, HeartMate XVE, HeartWare HVAD, and Jarvik 2000 in three patients with D-TGA and three with CC-TGA [55••]. The EXCOR Berlin Heart, commonly used in pediatric patients who are too small for an implantable VAD, has not been reported as frequently for use in ACHD patients. While the use of a VAD as a bridge to transplantation has increased significantly over the last 30 years in patients without CHD, no similar increase has been seen among

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ACHD patients [56•]. The exact reason for this difference is unclear, but it may reflect the fact that clinical HF in patients with ACHD—particularly in the case of failing Fontan—can be caused not only by pump failure, but also by circulatory compromise from chronically elevated venous pressure. There are other such situations in which both ventricles are failing or when a single VAD is not sufficient. This may be remedied by placement of biventricular VADs, usually a left VAD followed by a right VAD. Another option is the total artificial heart (TAH), a device that provides up to 10 L/min of flow in a biventricular fashion. The SynCardia TAH has now been implanted in over 50 patients younger than 21 years and in more than 20 patients with ACHD [57•].

Transplantation Heart transplantation may be considered as a viable treatment option for endstage disease in patients with ACHD. Transplant numbers have increased by 41 % over the past two decades [58]. As HF is the leading contributor to late mortality in this population, a substantial number of patients may be considered for heart transplant. It is estimated that up to 20 % of ACHD patients may require heart or heart-lung transplantation. However, given the diverse cohort of patients, with frequently complex disease involving multiple organ systems in the setting of prior thoracic surgeries, the consideration to pursue transplantation must be approached thoughtfully. ACHD patients listed for heart transplant are typically younger than other adults listed and have a lower body mass index as well as fewer comorbidities [59]. In a recent investigation of the impact of ACHD on survival, Burchill and colleagues [60••] identified 1,851 ACHD patients who underwent cardiac transplant during the period between 1985 and 2010 from an analysis of the International Society for Heart and Lung Transplantation (ISHLT) registry. Outcomes for ACHD patients were compared to a control group of adult recipients transplanted for other etiologies. Of the 85,467 adults who received a heart transplant, only 1,851 (2.2 %) had CHD. Interestingly, there was an increase in the number of ACHD transplants between the eras of 1984-1994 and 2005-2010. ACHD heart transplant patients were younger, had a lower body mass index and fewer comorbidities such as diabetes or renal dysfunction, and had a higher proportion of females compared to controls. Survival for the ACHD group at 1, 5, 10, and 15 years was 77 %, 67 %, 57 %, and 53 %, respectively, while survival in the control group was 83 %, 70 %, 53 %, and 37 % (pG0.0001 across all comparisons). The most common causes of death in the first year in both groups were graft failure, infection, acute rejection, and multiorgan failure. The relationship between age and mortality risk was non-linear, with the highest rates of mortality in patients aged 2530 years. In an analysis of recipient characteristics to assess for early ACHD transplant recipient mortality, cardiac retransplantation was the only independent predictor of mortality within five years of undergoing a transplant procedure, conditional on survival to one year, in patients whose first heart transplant was for CHD. In addition, ACHD patients who underwent retransplantation had worse late outcomes, with a 2.75-fold increase in the hazard ratio for mortality compared to primary heart transplant patients. This report supports previous findings that early mortality is increased in ACHD transplant patients, which may be related to multiple prior thoracic surgeries [60••]. There are


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important lessons from the Burchill et al. data, the largest report to date assessing transplant outcomes in ACHD. The continued documentation of early transplant mortality must be considered and targeted for new management strategies. Long-term survival, dependent on one year conditional survival, is better than for non-ACHD adult transplant populations, and the use of cardiac retransplantation must be considered carefully, as mortality in this group is high. Heart transplant continues to be a viable option, with an apparent “survival paradox,” with increased early mortality but better long-term conditional survival compared to nonACHD adults. Given the increasing complexity of the ACHD population, and in light of advancements in the field, multiorgan transplantation may also be a consideration. A recent report from the Mayo Clinic detailed their single-center experience with transplantation for end-stage CHD [61•]. Of 45 patients undergoing transplant procedures (age range, 1 month to 65 years), three patients underwent successful combined-organ transplant (two heart/liver and one heart/kidney). This report, as well as those by others, demonstrates that multiorgan transplant can be successfully pursued for patients with ACHD, with careful management and consideration of appropriate recipients.

Novel treatment strategies Promising novel treatments in the CHD population include stem cell therapy in patients with single ventricle physiology and the continued use of the TAH in the ACHD population. Stem cell therapy in acquired ischemic cardiac disease has shown improvement in LV function and infarct size, as well as favorable cardiac remodeling [62]. Although limited, pediatric studies using stem cell therapy in patients with single ventricle defects have shown improvement in RVEF [61]. In the Phase I TICAP (Transcoronary Infusion of Cardiac Progenitor Cells in Patients with Single Ventricle Physiology) trial, 7 of the 14 patients showed improvement in RV systolic function [61]. The current phase II PERS EUS trial plans to enroll 34 patients with single ventricle anatomy in order to further this investigation of stem cell therapy by evaluating ejection fraction using echocardiography, ventriculography, and cardiac MRI, including delayed gadolinium enhancement to assess for fibrosis [63]. The SynCardia TAH has been used successfully as a bridge to transplant in certain ACHD patients who are refractory to medical therapy. Unfortunately, for our pediatric and young adult population, the SynCardia TAH utilizing two 70-ml ventricles is recommended for BSA greater than 1.7 m2 (Table 2), thereby excluding a significant portion of the population based on size. The recently developed SynCardia TAH utilizing two 50-ml ventricles, which is recommended for BSA greater than 1.2 m2, provides a new option for long-term support as a bridge to transplant in this population.

Conclusions ACHD presents a unique set of management challenges. The heterogeneity of the population has resulted in limited opportunities for clinical research. However, the field is evolving, with growing interest in focused and multicenter

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research. Multicenter study enrollment is necessary and facilitated by visiting the clinical studies website ( where a list of current ACHD studies can be found. Although appropriate in certain patients, traditional management strategies for adult myocardial dysfunction applied to the ACHD population must be approached thoughtfully, as they may not have the desired effect. Traditional risk factors for cardiovascular disease should be assessed frequently, with intervention when appropriate, as they offer one possible area for favorable impact on future morbidity and mortality. The complex milieu of management of HF in ACHD necessitates the involvement of specialists in ACHD care. The growing armamentarium of diagnostic and therapeutic tools in cardiac care provides exciting opportunities for investigation in the diverse and rapidly expanding population of individuals with ACHD.

Compliance with Ethics Guidelines Conflict of Interest T.D. Ryan, J.L. Jefferies, and I. Wilmot each declare no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest have been highlighted as: • Of importance •• Of major importance 1. 2.

3. 4. 5.

Gross RE. Surgical management of the patent ductus arteriosus: with summary of four surgically treated cases. Ann Surg. 1939;110:321–56. Blalock A, Taussig HB. Surgical treatment of malformations of the heart; in which there is pulmonary stenosis or pulmonary atresia. JAMA. 1945;128:189–202. Gibbon Jr JH. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med. 1954;37:171–85. passim. Hoffman JI, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. Am Heart J. 2004;147:425– 39. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Developed in collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital

Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52:e143–263. 6. Perloff JK. Pediatric congenital cardiac becomes a postoperative adult. The changing population of congenital heart disease. Circulation. 1973;47:606–19. 7.• O’Leary JM, Siddiqi OK, de Ferranti S, Landzberg MJ, Opotowsky AR. The changing demographics of congenital heart disease hospitalizations in the United States, 1998 through 2010. JAMA. 2013;309:984–6. Using the Nationwide Inpatient Sample, ICD-9 codes were employed to characterize inpatient hospital admissions for ACHD from 1998-2010, separated into the eras 1998-2004 and 2004-2010. During that time, the number of adult admissions doubled, and grew at a greater rate than that for children with CHD. 8.• Rodriguez 3rd FH, Moodie DS, Parekh DR, Franklin WJ, Morales DL, Zafar F, et al. Outcomes of heart failure-related hospitalization in adults with congenital heart disease in the United States. Congenit Heart Dis. 2013;8:513–9. Again using the Nationwide Inpatient Sample, this manuscript demonstrated that HF-related hospital admissions were


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common for patients with ACHD. More importantly, the risk for death, compared to ACHD patients without HF, was higher. 9. Verheugt CL, Uiterwaal CS, van der Velde ET, Meijboom FJ, Pieper PG, van Dijk AP, et al. Mortality in adult congenital heart disease. Eur Heart J. 2010;31:1220–9. 10. Shaddy RE, Webb G. Applying heart failure guidelines to adult congenital heart disease patients. Expert Rev Cardiovasc Ther. 2008;6:165–74. 11.• Krieger EV, Valente AM. Heart failure treatment in adults with congenital heart disease: where do we stand in 2014? Heart. 2014;100:1329–34. A review article summarizing current literature in the ACHD population with HF, and summarizing CRT and ICD literature in this field. 12. Norozi K, Wessel A, Alpers V, Arnhold JO, Geyer S, Zoege M, et al. Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery. Am J Cardiol. 2006;97:1238–43. 13. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235. 14.•• Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Dwriting committee to develop guidelines on the management of adults with congenital heart disease]. Circulation. 2008;118:2395–451. A reference for management of ACHD patients. The ACC/AHA guidelines on the management of ACHD patients with HF provides some the limited evidence to support current guidelines. 15. Broberg CS, Aboulhosn J, Mongeon FP, et al. Prevalence of left ventricular systolic dysfunction in adults with repaired tetralogy of Fallot. Am J Cardiol. 2011;107:1215–20. 16. Ghai A, Silversides C, Harris L, et al. Left ventricular dysfunction is a risk factor for sudden cardiac death in adults late after repair of tetralogy of Fallot. J Am Coll Cardiol. 2002;40:1675–80. 17. Doughan AR, McConnell, Book WM. Effect of beta blockers (carvedilol or metoprolol XL) in patients with transposition of great arteries and dysfunction of the systemic right ventricle. Am J Cardiol. 2007;99:704–6. 18. Newburger JW, Sleeper LA, Bellinger DC, Goldberg CS, et al. Early developmental outcome in children with

Curr Treat Options Cardio Med (2015) 17:5 hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial. Circulation. 2012;125:2081–91. 19. Junge C, Westhoff-Bleck M, Schoof S, Danne F, Buchhorn R, Seabrook JA, et al. Comparison of late results of arterial switch versus atrial switch (mustard procedure) operation for transposition of the great arteries. Am J Cardiol. 2013;111:1505–9. 20. Tangcharoen T, Bell A, Hegde S, Hussain T, Beerbaum P, Schaeffter T, et al. Detection of coronary artery anomalies in infants and young children with congenital heart disease by using MR imaging. Radiology. 2011;259(1):240–7. 21.• Tutarel O. Acquired heart conditions in adults with congenital heart disease: a growing problem. Heart. 2014;100D17]:1317–21. The manuscript by Tutarel et al. underscores the important considerations of acquired cardiovascular disease in the ACHD population and potential targets for interventions. 22.• Afilalo J, Therrien J, Pilote L, Ionescu-Ittu R, Martucci G, Marelli AJ. Geriatric congenital heart disease: burden of disease and predictors of mortality. J Am Coll Cardiol. 2011;58D14]:1509–15. The manuscript by Afilalo et al. characterizes the shift in age of the CHD population and recognizes a growing cohort of patients over the age of 65. 23. Roifman I, Therrien J, Ionescu-Ittu R, Pilote L, Guo L, Kotowycz MA, et al. Coarctation of the aorta and coronary artery disease: fact or fiction? Circulation. 2012;126(1):16–21. 24. Zomer AC, Vaartjes I, Uiterwaal CS, van der Velde ET, Sieswerda GJ, Wajon EM, et al. Social burden and lifestyle in adults with congenital heart disease. Am J Cardiol. 2012;109(11):1657–63. 25. Fyfe A, Perloff JK, Niwa K, Child JS, Miner PD. Cyanotic congenital heart disease and coronary artery atherogenesis. Am J Cardiol. 2005;96(2):283–90. 26. Norozi K, Bahlmann J, Raab R, et al. A prospective, randomized, double blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot. Cardiol Young. 2007;17:372–9. 27. Babu-Narayan SV, Uebing A, Davalouros PA, et al. Randomised trial of ramipril in repaired tetralogy of Fallot and pulmonary regurgitation: the APPROPRIATE study (Ace inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation in Adults with repaired Tetralogy of Fallot). Int J Cardiol. 2012;154:299– 305. 28. Tobler D, Crean AM, Redington AN, Van Arsdell GS, et al. The left heart after pulmonary valve replacement in adults late after tetralogy of Fallot repair. Int J Cardiol. 2012;18:165–70. 29. Giardini A, Balducci A, Specchia S, et al. Effect of sildenafil on hemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29:1681–7.

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Sperling DR, Dorsey TJ, Rowen M, Gazzaniga AB. Percutaneous transluminal angioplasty of congenital coarctation of the aorta. Am J Cardiol. 1983;51:562–4. 46. Bonhoeffer P, Boudjemline Y, Saliba Z, Merckx J, Aggoun Y, Bonnet D, et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonaryartery prosthetic conduit with valve dysfunction. Lancet. 2000;356:1403–5. 47.•• Cullen MW, Cabalka AK, Alli OO, Pislaru SV, Sorajja P, Nkomo VT, et al. Transvenous, antegrade Melody valve-in-valve implantation for bioprosthetic mitral and tricuspid valve dysfunction: a case series in children and adults. JACC Cardiovasc Interv. 2013;6:598– 605. With proven use of the Melody valve in the pulmonary position established, this manuscript focuses on 19 patients with mitral or tricuspid dysfunction who underpent implantation. The Melody valve was successfully placed in all patients, with improvement in antegrade gradient and regurgitation score. This demonstrates the feasibility of other applications for the technique in ACHD patients. 48.•• Hasan BS, McElhinney DB, Brown DW, Cheatham JP, Vincent JA, Hellenbrand WE, et al. Short-term performance of the transcatheter Melody valve in high-pressure hemodynamic environments in the pulmonary and systemic circulations. Circ Cardiovasc Interv. 2011;4:615–20. This review looks at the experience from five centers involved in the IDE for placement of the Melody valve in high-pressure systems. In all, implantation of 30 devices showed promise for use in such a setting. 49. Martin MH, Gruber PJ, Gray RG. Transcatheter neoaortic valve replacement utilizing the Melody valve in hypoplastic left heart syndrome. Catheter Cardiovasc Interv. 2014. doi:10.1002/ccd.25472. 50. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–8. 51. Morales DL, Dibardino DJ, Braud BE, Fenrich AL, Heinle JS, Vaughn WK, et al. Salvaging the failing Fontan: lateral tunnel versus extracardiac conduit. Ann Thorac Surg. 2005;80:1445–51. discussion 1451-1442. 52. Delmo Walter EM, Hetzer R. Surgical treatment concepts for end-stage congenital heart diseases. HSR Proc Intensive Care Cardiovasc Anesth. 2013;5:81–4. 53. Zomer AC, Uiterwaal CS, van der Velde ET, Tijssen JG, Mariman EC, Verheugt CL, et al. Mortality in adult congenital heart disease: are national registries reliable for cause of death? Int J Cardiol. 2011;152:212–7. 54. Mulukutla V, Franklin WJ, Villa CR, Morales DL. Surgical device therapy for heart failure in the adult with congenital heart disease. Heart Fail Clin. 2014;10:197– 206. 55.•• Shah NR, Lam WW, Rodriguez 3rd FH, Ermis PR, Simpson L, Frazier OH, et al. Clinical outcomes after ventricular assist device implantation in adults with complex congenital heart disease. J Heart Lung Transplant. 2013;32:615–20.


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The largest case series of implantation of VAD in ACHD, compiled from a single center. In total, 6 patients representing 4 devices are reported. The series discusses important postoperative management challenges. However with a small sample size few definitive conclusions can be drawn. 56.• Gelow JM, Song HK, Weiss JB, Mudd JO, Broberg CS. Organ allocation in adults with congenital heart disease listed for heart transplant: impact of ventricular assist devices. J Heart Lung Transplant. 2013;32:1059– 64. Review of the UNOS database shows use of VAD in CHD patients to be less common than in non-CHD. This reduced used contributes to lower listing status overall and affected organ allocation. 57.• Ryan TD, Jefferies JL, Zafar F, Lorts A and Morales DL. The evolving role of the total artificial heart in the management of end-stage congenital heart disease and adolescents. ASAIO J. 2015;61(1):8–14. History of the TAH in ACHD, including data about implantation of a single type of device (SynCardia) and a case report of use in an adolescent patient. 58. Karamlou T, Hirsch J, Welke K, Ohye RG, Bove EL, Devaney EJ, et al. A United Network for Organ Sharing analysis of heart transplantation in adults with congenital heart disease: outcomes and factors associated with mortality and retransplantation. J Thorac Cardiovasc Surg. 2010;140(1):161–8. 59. Davies RR, Russo MJ, Yang J, Quaegebeur JM, Mosca RS, Chen JM. Listing and transplanting adults with

Curr Treat Options Cardio Med (2015) 17:5 congenital heart disease. Circulation. 2011;123(7):759–67. 60.•• Burchill LJ, Edwards LB, Dipchand AI, Stehlik J, Ross HJ. Impact of adult congenital heart disease on survival and mortality after heart transplantation. J Heart Lung Transplant. 2014;33D11]:1157–63. doi:10.1016/j. healun.2014.05.007. The manuscript by Burchill et al. is of significant importance in the ACHD community as it identifies important early and late transplant outcome data. Furthermore, their data implicate retransplantation as a potentially high risk consideration in management. 61.• Robinson JA, Driscoll DJ, O’Leary PW, Burkhart HM, Dearani JA, Daly RC, et al. Cardiac and multiorgan transplantation for end-stage congenital heart disease. Mayo Clin Proc. 2014;89D4]:478–83. The manuscipt by Robinson et al. offers more information about outcomes for transplantation in CHD populations but perhaps more importantly reports good outcomes in adults with CHD undergoing multiple organ transplantation. 62. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, ZubaSurma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and metaanalysis. Circulation. 2012;126(5):551–68. 63. Suguru T, Shunji S, Hidemasa O. Stem cell therapies in patients with single ventrilce physiology. Methodist DeBakey Cardiovasc J. 2014;10(2):77–81.

Managing heart failure in adults with congenital heart disease.

The current era of cardiology has seen a significant increase in the number of adults living with congenital heart disease (CHD). Although advances in...
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