E l e c t ro p h y s i o l o g i c T h e r a p e u t i c s i n H e a r t Fa i l u re i n Adult Congenital Heart Disease Kara S. Motonaga, MDa,*, Paul Khairy, MD, PhDb, Anne M. Dubin, MDa KEYWORDS  Arrhythmias  Electrophysiology  Heart failure  Adult congenital heart disease  Therapeutics  Antiarrhythmics  Device therapy  Resynchronization

KEY POINTS  Antiarrhythmic therapy is an important component of atrial arrhythmia management in the adult with congenital heart disease.  Device therapy including conventional pacing, antitachycardia pacing, cardioversion, and defibrillation can be useful for atrial and ventricular arrhythmias in patients with congenital heart disease.  Ablation of atrial and ventricular arrhythmias can decrease morbidity and mortality in this patient population. Advanced technologies including three-dimensional navigation systems and new energy sources can aid in successful ablation.  Surgical interventions to improve hemodynamics or to interrupt arrhythmia circuits can be a useful therapeutic option in selected adults with congenital heart disease.

With improvement in medical, interventional, and surgical therapies for congenital heart disease (CHD), most patients with CHD are surviving into adulthood such that there are now more adults living with CHD in the United States and Canada than there are patients with CHD younger than 18 years old.1 Survival of the patient with adult CHD (ACHD) continues to improve with decreasing mortality rates that parallel those of the general population.2 Despite these successes, heart failure remains one of the most common causes of morbidity and

mortality in ACHD.3–6 In 2007, heart failure accounted for 20% of all ACHD hospital admissions in the United States.7 Patients with ACHD with heart failure had a threefold increase in hospital mortality compared to those without heart failure. Not surprisingly, most patients with ACHD with heart failure die from cardiovascular causes, especially pump failure and arrhythmias.8 Fifty-two percent of patients with ACHD admitted with heart failure in the United States in 2007 also had arrhythmias.8 Management of arrhythmias, therefore, is a critical component of caring for the patient with ACHD with heart failure. These arrhythmias often result from surgical scars, as well as chronic volume and pressure

Financial Support: Dr P. Khairy is supported by a Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease. Conflict of Interest: Dr P. Khairy has received research funding for investigator-initiated grants from St. Jude Medical, Medtronic, and Boehringer-Ingelheim. Drs A.M. Dubin and K.S. Motonaga have received educational support from Medtronic Inc. a Pediatric Cardiology, Stanford University, 750 Welch Road, Suite 325, Palo Alto, CA 94304, USA; b Adult Congenital Heart Center and Electrophysiology Service, Montreal Heart Institute, Universite´ de Montre´al, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada * Corresponding author. Stanford University, 750 Welch Road, Suite 325, Palo Alto, CA 94304. E-mail address: [email protected] Heart Failure Clin 10 (2014) 69–89 http://dx.doi.org/10.1016/j.hfc.2013.09.011 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.




Motonaga et al loads, cyanosis, and chamber enlargement. Electrophysiologic therapeutic strategies in this population can include control of arrhythmias and prevention of sudden cardiac death (SCD) as well as preservation of cardiac function.

BRADYARRHYTHMIAS Sinus Node Dysfunction Congenital sinus node dysfunction may be seen in patients with CHD, such as those with heterotaxy with left atrial isomerism. These patients may lack a true sinus node altogether, which makes their heart rate dependent on slower atrial or junctional escape rhythms. More commonly, however, sinus node dysfunction is a result of surgical trauma to the sinoatrial node or its artery, which may occur during the atrial switch procedure (Mustard or Senning procedures) for d-transposition of the great arteries (d-TGA) or single-ventricle palliation with a Glenn or Fontan procedure.9–12 In patients with Mustard procedures for d-TGA, symptomatic sinus node dysfunction is observed in 64% and 82% at 5 and 16 years of follow-up, respectively.13 Chronotropic incompetence may be poorly tolerated in patients with ACHD with compromised hemodynamics, especially those with a single ventricle or significant atrioventricular (AV) valve regurgitation. The likelihood of a patient developing intra-atrial reentrant tachycardia (IART) or atrial fibrillation is also increased significantly in this setting, which can result in the induction of secondary ventricular tachycardia and SCD.9,14 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) 2012 guidelines recommend permanent pacing for symptomatic age-inappropriate bradycardia (class I, level of evidence B), tachy-brady syndrome with recurrent IART (class IIa, level of evidence C), sinus bradycardia in the setting of complex CHD with resting heart rate less than 40 bpm or pauses in ventricular rate longer than 3 seconds (class IIa, level of evidence C), or CHD and impaired hemodynamics caused by sinus bradycardia or loss of AV synchrony (class IIa, level of evidence C).15

AV Node Dysfunction Patients with AV discordance have a 2% incidence of developing spontaneous AV block on an annual basis.16 AV nodal conduction defects, however, are more commonly the sequelae of intracardiac repair (1%–3% of congenital heart surgeries), typically involving the ventricular septum.17–20 In a study of adult patients with heart failure with a single or systemic right ventricle, 72% of symptomatic patients had a history of heart block. Of

those who died with heart failure, 76% had second-degree AV block or higher and 62% required a pacemaker. ACC/AHA/HRS 2012 guidelines recommend permanent pacing for advanced second-degree or third-degree AV block associated with symptomatic bradycardia, ventricular dysfunction, or low cardiac output (class I, level of evidence C), postoperative advanced second-degree or thirddegree AV block that is not expected to resolve or that persists at least 7 days after cardiac surgery (class I, level of evidence B), or congenital third-degree AV block with a ventricular rate less than 70 bpm in the setting of CHD (class I, level of evidence C). When permanent pacing is indicated, challenges include lack of or obstructed venous access, obstructed baffles or conduits, baffle leaks, difficulties in lead positioning, high rates of lead complications, and coexisting intracardiac shunts.21–23 Single-site ventricular pacing, even from the subpulmonary left ventricle (LV) in this setting, results in an obligatory dyssynchronous ventricular contraction that may be associated with a reduction in ventricular performance over time. Pacemaker implantation has been proposed as a risk factor for mortality after the first heart failure admission in adults with CHD.8,24 Patients with CHD and devices face a lifelong prospect of potential device and lead-related complications, often requiring multiple reinterventions.22 Given the high incidence of lead failure in an aging patient population, lead extraction procedures are increasingly required in adults with CHD.25 Particular challenges are encountered in this population. In a cohort of 175 adults with attempted laser extraction of 270 leads, those with CHD were younger at implantation, had older leads at extraction, more right-sided implants, a higher proportion of active fixation leads, and had particular anatomic features including intracardiac shunting, leads in subpulmonary LVs, left atrial (LA) appendages, severely dilated and/or dysfunctional subpulmonary right ventricles (RVs), and partially obstructed baffles.26 Despite these complexities, success rates (91%) and complication rates (6%) were similar to those in patients without CHD, although a longer procedural time was required.26

ATRIAL TACHYARRHYTHMIAS Intra-atrial Reentrant Tachycardia IART is the most common symptomatic sustained tachyarrhythmia in the ACHD population.11,27 The terms intra-atrial reentrant tachycardia and incisional tachycardia have become customary labels

Electrophysiologic Therapeutics in Heart Failure for this arrhythmia to distinguish it from the typical variety of cavotricuspid isthmus (CTI) atrial flutter that occurs in structurally normal hearts.28–30 Regions of fibrosis from suture lines or patches function in combination with natural conduction barriers (crista terminalis, valve orifices, and the superior and inferior caval orifices) to channel the wavefront of propagation along a macroreentrant loop.31–33 Multiple coexisting IART pathways are possible, with varying circuits that are dependent, in part, on the anatomic defect and type of surgical repair.34–36 IART typically has a slower atrial rate (150– 250 bpm) than typical CTI flutter, which may favor 1:1 conduction that can lead to hemodynamic instability and cardiac arrest in patients with ACHD with heart failure.37 It is most often seen in older Fontan patients with atriopulmonary connections (up to 50%–60%) or lateral tunnels (20%– 30%),9,38–42 patients with Mustard or Senning atrial baffles for d-TGA (w30%),10 or patients with tetralogy of Fallot (TOF; up to one-third),43 but can also occur with repair of simple cardiac defects such as an atrial septal defect.44,45 Other risk factors for IART include concomitant sinus node dysfunction (tachy-brady syndrome) and older age at time of heart surgery.9

Atrial Fibrillation The prevalence of atrial fibrillation (AF) is increasing in the aging population with CHD and is significantly higher than in the general adult population with an earlier age of onset.46 In patients with TOF, AF surpasses IART as the most common atrial tachyarrhythmia in patients older than 55 years of age.47 AF is associated predominantly with markers of left-sided heart disease, lower LV ejection fraction, and LA dilation.47,48 In addition, patients with ACHD with AF frequently have a previous history of IART.46 The specific cause and mechanism of AF in ACHD remain to be elucidated. Extrapolating from literature on AF in adults with structurally normal hearts, AF may be the result of random atrial microreentry.49 It is likely related to atrial size, atrial myocardial fibrosis from pressure/ volume loading or scarring related to surgery, and alterations in tissue refractoriness and/or automaticity.49 Hemodynamic instability can occur in the setting of a rapid ventricular response, particularly in patients with heart failure. Management principles are similar to AF encountered in other forms of adult heart disease, beginning with anticoagulation and ventricular rate control, and typically followed by electrical or medical cardioversion.

Acute treatment of IART and AF by electrical means (direct current cardioversion or overdrive pacing) or chemical means (class I or III antiarrhythmics) is effective, but maintenance of sinus rhythm in the long-term is challenging. Therapeutic options for recurrent atrial arrhythmias include (1) antiarrhythmic drugs, (2) catheter ablation, (3) pacemaker implantation for tachy-brady syndrome or to provide automatic atrial antitachycardia pacing (ATP), and (4) surgical intervention with a modified atrial maze or Cox-Maze operation. The choice must be tailored to the hemodynamic and electrophysiologic status of the individual patient.27,50

Pharmacologic Therapy for Atrial Arrhythmias There is only minimal data on the efficacy and safety of antiarrhythmic drugs in the ACHD population, however, experience and extrapolation from adult series adds to information from smaller pediatric CHD series on antiarrhythmic therapy. Medications can be categorized into those that suppress arrhythmia versus those that are given for ventricular rate control. Selecting an appropriate antiarrhythmic therapy is a unique challenge and requires careful consideration of several factors in the ACHD heart failure population because of undesirable side effects (such as concomitant bradyarrhythmia, negative inotropic effects, and proarrhythmia effects that may be enhanced in the setting of heart failure). Class II and class IV antiarrhythmic agents (AV nodal blocking agents) b-Blockers and calcium channel blockers are primarily used for rate control as well as suppression of atrial ectopic beats that may act as triggers for atrial tachycardias. Calcium-channel blockers should be used with caution in patients with ACHD with heart failure because of negative inotropic effects. b-Blockers are the drug of choice for rate control in the setting of heart failure.51 Both b-blockers and calcium channel blockers should be used cautiously in patients with the potential for sinus bradycardia or heart block. Class I antiarrhythmic agents Sodium channel blockers, which are often used to suppress atrial tachyarrhythmias, should be considered contraindicated in the patient with ACHD with heart failure because of their proarrhythmic potential and negative inotropic effects.52 Proarrhythmia effects of flecainide and propafenone were significantly increased in pediatric patients with CHD as well as adult patients with heart failure, resulting in increased mortality.53–55



Motonaga et al Class III antiarrhythmic agents In contrast, class III antiarrhythmic agents may be considered in patients with CHD and heart failure.56–58 Sotalol has been widely used in the management of atrial arrhythmias for several decades, including in patients with CHD.56–60 The incidence of proarrhythmia side effects, however, has been as high as 10% in one pediatric cohort, including sinus bradycardia, heart block, torsades de pointes, and increased ventricular ectopy.61 Sotalol should, therefore, be used with caution in the patient with ACHD with heart failure. Another class III antiarrhythmic agent commonly used for chronic suppression of atrial tachyarrhythmias is amiodarone. Amiodarone is predominantly a potassium channel blocker but also exhibits a-receptor and b-receptor antagonism and results in prolongation of the QT interval. However, torsades de pointes is uncommon.62 Amiodarone is typically well tolerated in patients with CHD and ventricular dysfunction with little or no negative inotropic effects.63–65 Nevertheless, its use may be limited by the potential for noncardiac toxicity, which to some extent is dose and duration dependent. Abnormalities in thyroid function may be seen in up to one-third of patients with ACHD.64 Risk factors for thyroid dysfunction in the patient with CHD include female gender, cyanotic CHD, previous Fontan repair, and an amiodarone dose greater than 200 mg/day.66 Other adverse effects of amiodarone include hepatic dysfunction, pulmonary toxicity, photosensitivity, optic neuropathy, and neurologic changes.62 In general, maintenance of sinus rhythm with pharmacologic management of atrial flutter and AF alone is often problematic.67–71 Amiodarone has consistently been shown to be more efficacious than other antiarrhythmic drugs with up to 75% to 85% suppression of AF and atrial flutter at 1 year,67,68,71–74 but there remains a 50% recurrence rate by 3 to 5 years.73,74

Catheter Ablation for Atrial Arrhythmias Catheter ablation is commonly used at many centers for intervention and treatment of atrial flutter and AF, particularly when antiarrhythmic drugs fail or are poorly tolerated. Advances in threedimensional (3D) mapping techniques and catheter technologies have provided new optimism for arrhythmia management in adults with CHD. With a thorough understanding and appreciation for underlying structural disease, surgical barriers, tenuous physiology, and variations in conduction system anatomy, most arrhythmias can be safely and successfully ablated.75,76 Particular challenges may be numerous including compromised

vascular access because of previous venous cutdowns and/or multiple interventions during childhood. The chamber of interest may be formidably large, as in the atriopulmonary Fontan connections, with difficulties in ensuring optimal catheter contact and transmural lesions. Baffle or conduit obstructions and acute angles may impede access to areas of interest. Punctures across conduits or surgical patches may be required in TGA with intra-atrial baffles, univentricular hearts with total cavopulmonary connections, and surgically repaired atrial septal defects. Many centers are now using catheter ablation as an early intervention for IART in preference to longterm drug therapy in patients with CHD.34,77,78 Combining 3D electroanatomic mapping with good anatomic definition and traditional electrophysiologic maneuvers, acute success rates for IART ablation in CHD may exceed 80%.34,77,78 Onset of new tachyarrhythmias and recurrences remain problematic, particularly among Fontan patients (nearly 40% at 2 years), who tend to have multiple IART circuits and thick and large atria.77 Although far from perfect, ablation outcomes for IART are likely to improve with continued experience and seem superior to the degree of control obtained with medications alone. Even if IART episodes are not eliminated entirely by ablation, the procedure can reduce symptoms, improve quality of life, and eliminate the need for ongoing drug therapy.77 More recently, robotic systems for catheter ablation have been introduced into clinical practice.79 With magnetic-guided systems, very soft and flexible ablation catheters can be navigated toward otherwise unattainable areas.79–81 Initial series in patients with CHD have demonstrated the feasibility of ablating complex circuits across baffles and conduits with high (>85%) acute success rates with this technology.82,83 Catheter ablation for AF involves electrical isolation of the pulmonary veins from the left atrium. Risks include pulmonary vein stenosis, pericardial tamponade, stroke, and atrial-esophageal fistula formation.84 Outcomes in ACHD remain to be defined. In a series of 36 patients with primarily simple CHD lesions compared with 355 controls without CHD, single procedural success at 300 days was achieved in 42% of patients with CHD compared with 53% of controls.85 By 4 years of follow-up, the corresponding success rates were 27% and 36%, respectively. Adverse events were similar (15% vs 11%) except for more frequent vascular complications in patients with CHD (8% vs 1%, P

Electrophysiologic therapeutics in heart failure in adult congenital heart disease.

Arrhythmias have long been recognized as a major cause of morbidity and mortality in the adult with congenital heart disease. It is important that the...
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