7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Heart transplantation in adults: Arrhythmias : Howard J Eisen, MD, FACC, FAHA, FHFSA, FAST, Luke S Kusmirek, MD, FACC : Sharon A Hunt, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 03, 2021. INTRODUCTION Cardiac arrhythmias are common in the orthotopic heart transplant recipient, particularly in the early postoperative period. Premature atrial complexes and premature ventricular complexes are especially frequent, with a reported incidence of over 60 percent. Fortunately, these arrhythmias have little clinical importance. However, other cardiac arrhythmias, such as sinus node dysfunction and ventricular tachycardia, may result in significant morbidity or mortality. Prognosis and other clinical issues following cardiac transplantation are discussed separately. (See "Heart transplantation in adults: Prognosis" and "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy" and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy" and "Heart transplantation in adults: Graft dysfunction" and "Heart transplantation in adults: Diagnosis of allograft rejection" and "Heart transplantation in adults: Treatment of acute allograft rejection" and "Heart transplantation in adults: Exercise-based rehabilitation for transplant recipients" and "Heart transplantation in adults: Pregnancy after transplantation" and "Heart transplantation: Hyperlipidemia after transplantation" and "Malignancy after solid organ transplantation".) MECHANISMS There are several mechanisms for arrhythmogenesis in the transplanted heart, with early postoperative arrhythmias resulting from different mechanisms than those occurring later. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 1/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate Surgical trauma to the sinoatrial and atrioventricular nodes, ischemia during preservation, surgical suture lines, and, over the long term, rejection and accelerated atherosclerosis may contribute to the formation of an arrhythmogenic substrate. As an example, one autopsy study of 18 hearts found that acute rejection involved the conduction system as severely as the myocardium [1]. With chronic rejection, there was often obstructive vasculopathy of the sinus node artery. In occasional cases, severe rejection isolated to the conduction system with sparing of the rest of the myocardium occurs and presents as bradycardia with syncope [2]. In addition, the denervated donor heart has increased sensitivity to sympathetic amines, adenosine, and acetylcholine, which may contribute to both tachyarrhythmias and bradyarrhythmias [3-5]. The sympathetic effect may be presynaptic in origin; it is not due to increased beta receptor density [3,4]. Because of this increased sinus node sensitivity, adenosine should generally not be used (as it often used is in other patient populations) to slow the rate in supraventricular tachyarrhythmias to elucidate the underlying arrhythmia mechanism. Such use can result in prolonged bradycardia or a period of asystole. Cautious use of IV adenosine in selected pediatric and young adult transplant patients was well tolerated in one single center study [6]. SINUS RATE In the denervated heart, the normal resting sinus rate is usually greater than 80 bpm and may exceed 100 bpm in hearts transplanted from young donors. The heart rate is higher than in normals because of the loss of vagal neural inputs, which have a negative chronotropic effect. (See "Sinus tachycardia: Evaluation and management".) Partial reinnervation of cardiac sympathetic nerves after transplantation occurs in about one- third of patients at one year [7-10]. The process of reinnervation continues gradually for up to 15 years but is regionally heterogeneous [10,11]. Reinnervation of the sinus node is accompanied by partial restoration of the normal heart rate response to exercise [8,9]. Vagal innervation appears to be absent in the majority of patients for up to 96 months after transplant [12]. Vagal reinnervation may depend upon surgical technique; it occurs more commonly with bicaval compared with the standard biatrial surgery [13]. Standard biatrial surgery transects about 50 percent of sympathetic fibers, but most recipient vagus nerve trunks remain intact. As a result, there is a stimulus for sympathetic fiber, but not vagal fiber, https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 2/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate regeneration. In contrast, bicaval surgery transects both sympathetic and parasympathetic fibers and regeneration may be stimulated in both branches. Persistent post-transplant sinus tachycardia is associated with decreased long-term survival. The role of agents to reduce heart rate (beta blocker or ivabradine) in this setting has not been established. A preliminary observational study found that 2 year survival was higher in patients treated with ivabradine compared to patients treated with metoprolol [14]. Further study is required to determine the efficacy of these drugs in this setting. SINUS NODE DYSFUNCTION Prevalence and causes Sinus node dysfunction (SND), which is usually manifested by a relative bradycardia, occurs in up to 50 percent of patients in the first several weeks following transplantation [15-17]. Although this early abnormality does not appear to affect mortality [18,19], sinus bradycardia may result in significant morbidity from decreased cardiac output. In a series of 1179 heart transplants (91 percent with biatrial technique) performed over 35 years, 11.5 percent required pacemaker implantation to treat bradycardia; 86 percent of patients requiring a pacemaker had SND [19]. Independent risk factors for pacemaker implantation were prolonged operative time and a biatrial anastomosis. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation" and "Sinus node dysfunction: Epidemiology, etiology, and natural history".) In cardiac transplant recipients with SND, intact atrioventricular nodal function is usually present; thus, atrial pacing is often sufficient but usually delivered with a dual chamber pacemaker capable of ventricular backup pacing if needed [20]. Lead dislodgement during endomyocardial biopsy rarely occurs. (See "Permanent cardiac pacing: Overview of devices and indications".) Potential causes of SND include ischemia during hypothermic preservation; surgical trauma to the sinus node, perinodal atrial tissue, or sinoatrial artery; pretransplant use of amiodarone; and immunologic processes such as rejection [17,21]. In one series, for example, patients who required permanent pacemakers for sinus bradycardia had a significantly higher prevalence of abnormal sinoatrial nodal arteries when compared to a control group of heart transplant recipients with normal sinus node function [22]. Surgical trauma to the sinoatrial artery can be avoided by performing a bicaval anastomosis rather than the standard biatrial anastomosis [19,23,24]; thus, the bicaval technique has become the most commonly used procedure in transplant centers [25]. This technique consists of total excision of the right atrium with a minimum cuff of left atrium remaining around the four https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 3/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate pulmonary veins, followed by direct anastomoses of the donor and recipient vena cavae. It appears to be associated with a decreased incidence of SND [26-28]. In a prospective series of 70 orthotopic heart transplant recipients undergoing either a standard biatrial or a bicaval anastomosis, the incidence of SND, as determined by atrial pacing techniques, was much lower with bicaval anastomosis (5 versus 44 percent) [28]. This finding was confirmed in a United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database analysis of 20,999 recipients indicating that those transplanted utilizing bicaval anastomosis had lesser need for pacemaker therapy and improved long-term survival [29]. Several studies have suggested correlation of bradycardia with the donor ischemic time [16,30,31]; however, in other series, the donor ischemic time was not significantly different for orthotopic heart transplant recipients who required implantation of a permanent pacemaker for sinus bradycardia compared with those without this complication [19,22]. A separate UNOS/OPTN database analysis of 35,987 patients reported a 10.9 percent incidence of pacemaker-requiring bradyarrhythmias [32]. A biatrial anastomosis as well as greater recipient and donor age were the only factors associated with increased permanent pacemaker requirement. Pacemaker implantation had no adverse effect on survival; in fact, survival was better in pacemaker recipients as compared to those not receiving a pacemaker. Treatment of sinus bradycardia Normalization of post-transplant SND and bradyarrhythmias occurs spontaneously in up to 55 percent of patients during the first three postoperative months and a conservative strategy is reasonable in the early postoperative period [15]. The administration of theophylline [33,34] terbutaline [35], or albuterol has been advocated to increase the sinus rate and avoid implantation of a permanent pacemaker during the first three postoperative months. Studies comparing the acute effects of these agents, however, have demonstrated only a modest shortening of the sinus node cycle length and recovery time, with incomplete correction of the underlying sinus node abnormality [36,37]. Thus, these drugs are probably best reserved for patients with only mild or moderate SND or those with postoperative bradycardia due to prior amiodarone use. Atropine is not an effective treatment for bradycardia in the transplanted heart when vagal innervation is absent. Intravenous isoproterenol is suggested in the unlikely event that emergency treatment of bradycardia is needed in the heart transplant patient who does not have pacemaker wires in place. Patients with more severe bradycardia that persists for more than two weeks after transplantation usually require a permanent pacemaker; a rate-responsive dual chamber or https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 4/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate atrial pacemaker implanted in the donor right atrium (if intact atrioventricular conduction is present) is recommended [38]. (See "Modes of cardiac pacing: Nomenclature and selection".) The role of biventricular pacing is not known in cardiac transplant recipients who fulfill the criteria used for such therapy in nontransplant patients. Successful implementation of cardiac resynchronization therapy in heart transplant patients has been reported [39]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) CONDUCTION DISTURBANCES The most common conduction abnormality following orthotopic heart transplant is a new right bundle branch delay not present on the donor electrocardiogram (ECG) prior to transplantation. This can occur in up to 70 percent of patients and is usually manifest as an incomplete right bundle branch block present immediately postoperatively [40]. The conduction abnormality may persist and, in one study, was associated with prolonged donor ischemic time and multiple episodes of rejection [41]. These findings were corroborated in a later report in which early RBBB was correlated with transpulmonary gradient before orthotopic heart transplant and late occurrence was correlated with higher rejection scores [42]. The incidence of RBBB was higher with biatrial versus bicaval anastomosis. Potential mechanisms for later right bundle branch block include right ventricular hypertrophy from elevated pulmonary pressures or damage to the right bundle from endomyocardial biopsy sampling of the right ventricular septal wall. (See "Right bundle branch block".) Although the transplanted heart is denervated, atrioventricular (AV) nodal function is intact and the ability of the AV node to adapt to exercise with a shortening of the PR interval is retained since it remains sensitive to circulating catecholamines [43]. High grade AV block is uncommon, particularly in the early postoperative period [16]. Although pacemaker implantation is performed in approximately 10 to 15 percent of cardiac transplant recipients, AV block accounts for less than 20 percent of these cases [22,44,45] and median time to pacemaker implantation is later for AV block than for sinus node dysfunction (eg, 1511 versus 27 days [19]). The late development of heart block has been associated with an increase in mortality, often from transplant arteriopathy [46]. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Indications for pacemaker placement are the same as for other patients with symptomatic bradyarrhythmias or chronotropic incompetence that are not expected to resolve. Patients who undergo bicaval cardiac transplants are less likely to require permanent cardiac pacing than https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 5/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate those who undergo biatrial cardiac transplants [47] (see "Permanent cardiac pacing: Overview of devices and indications"). SUPRAVENTRICULAR ARRHYTHMIAS Atrial premature beats Isolated premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) and nonsustained atrial dysrhythmias are common in the early postoperative period, occurring in up to 76 percent of patients [16,48,49]. (See "Supraventricular premature beats".) The prevalence is lower at long-term follow-up, decreasing from 55 percent in the early postoperative period to 30 percent at mean of 24 months after transplantation in one report [48]. There are conflicting data on whether PACs occur with increased frequency during episodes of rejection [49,50]. Atrial fibrillation or flutter Reports of patients with atrial fibrillation (AF) or atrial flutter following cardiac transplantation have variably included perioperative and late arrhythmia. Atrial fibrillation has been described in 10 to 24 percent of patients [51-53], while atrial flutter has been described in 12 to 15 percent [49,53]. These arrhythmias often occur in the absence of significant rejection, although this has not been found in all reports [49,51,52,54]. Most episodes of AF occur within the first 30 to 60 days after transplantation with incidence ranging from 5 to 11 percent in large, single center experiences. This relatively low rate, compared to typical post-pericardiectomy AF incidence is postulated to be due to surgical pulmonary vein isolation and cardiac denervation, which occurs with the heart transplantation surgery. Patients treated with long-term amiodarone therapy prior to heart transplantation have less early postoperative atrial fibrillation with no adverse impact on mortality [55]. Late AF develops in 5 to 10 percent of patients and is associated with decrease in systolic function and increased overall mortality [51,53,56,57]. Atrial flutter may be a more common late arrhythmia [49]. Atrial flutter that occurs in the absence of rejection is a result of a macroreentrant circuit in a counterclockwise direction around the tricuspid ring, similar to that seen in typical atrial flutter in normal hearts [58-60]. This circuit includes the isthmus between the tricuspid valve and the inferior vena cava, referred to as the cavotricuspid isthmus. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) The cause of atrial dysrhythmias during rejection is not known. It is possible that the patchy nature of rejection results in heterogeneous impairment of atrial conduction and refractoriness, https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 6/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate allowing for the formation of multiple microreentrant circuits. In addition, atrial hemodynamics may be altered by the reduced ventricular function and compliance that occur during rejection. (See "The electrocardiogram in atrial fibrillation".) Treatment of these arrhythmias includes control of the ventricular response rate and, if warranted, immunosuppressive therapy for rejection. Overdrive pacing can be performed at the time of myocardial biopsy with more than a 90 percent success in terminating atrial flutter [54]. There are case reports and small series of successful radiofrequency ablation of atrial flutter in transplanted hearts [59,60]. Interestingly, the usual suture line between the donor and recipient heart lies within the cavo-tricuspid isthmus, which, as noted above, is a critical component of the circuit of typical atrial flutter. In a series of six cardiac transplant recipients undergoing cardiac electrophysiologic studies (EPS) for atrial flutter, only the tissue below the suture line from the donor heart was part of the macroreentrant circuit. In all of these cases, ablation from the tricuspid annulus to the suture line, rather than all the way to the inferior vena cava (IVC), successfully eliminated atrial flutter [60]. Macroreentry based on the gaps in the atrial anastomosis line and microreentrant/focal atrial tachycardias successfully treated with radiofrequency ablation have been described [61,62]. (See "Restoration of sinus rhythm in atrial flutter".) Heart transplant guidelines do not discuss anticoagulation in the setting of heart transplant patients with atrial fibrillation or atrial flutter. Standard guidelines for anticoagulation in patients with atrial fibrillation or atrial flutter should be followed in heart transplant patients. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Supraventricular tachycardias A variety of supraventricular arrhythmias can occur in orthotopic heart transplant recipients, including atrioventricular (AV) reentrant tachycardia involving a concealed AV bypass tract [63-65], Wolff-Parkinson-White syndrome [66,67], and sustained atrial tachycardias [52,68]. Radiofrequency catheter ablation has been performed in many of these patients with success and complication rates similar to nontransplant recipients [65,67,68]. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation" and "Overview of catheter ablation of cardiac arrhythmias", section on 'Introduction'.) Interaction of diltiazem with immunosuppressive agents Clinicians should be aware of drug interaction between diltiazem and immunosuppressive agents. Intravenous diltiazem is often used to control ventricular rates in patients with SVTs and/or atrial fibrillation. Diltiazem inhibits CYP3A, which metabolizes tacrolimus and cyclosporine. Consequently, heart transplant https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 7/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate patients receiving diltiazem often have elevated tacrolimus or cyclosporine levels which can result in renal dysfunction [69]. VENTRICULAR ARRHYTHMIAS Ventricular premature beats and nonsustained ventricular tachycardia Ventricular premature beats (VPBs) are common in the early post-transplant period, occurring in up to 100 percent of patients [16,49]. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation".) The incidence of VPBs decreases after the early postoperative period and does not appear to be associated with rejection or other factors. The frequency of nonsustained ventricular tachycardia (NSVT) also decreases over time [48]. However, some studies have demonstrated an association with both rejection and coronary atherosclerosis (cardiac allograft vasculopathy) [16,70]. In one small series, for example, complex ventricular ectopy (multifocal VPBs and couplets) occurring in the late transplant period was also more prevalent in patients with severe cardiac allograft vasculopathy [50]. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Sustained ventricular arrhythmias and sudden cardiac death Standard recommendations for ICD therapy apply to cardiac transplant recipients. Antiarrhythmic drug therapy is based on safety, tolerability, and clinical experience as limited published evidence is available for these drugs in cardiac transplant recipients. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) Sustained ventricular arrhythmias are uncommon in the donor heart; when they occur, they are usually associated with either severe transplant cardiac allograft vasculopathy or allograft rejection [71]. Ventricular fibrillation has been reported in patients hospitalized for severe allograft rejection [72,73], while autopsy studies of patients with sudden cardiac death have demonstrated a high prevalence of severe cardiac allograft vasculopathy or recent myocardial infarctions [72,74]. Although ventricular tachyarrhythmias are thought to be the mode of sudden cardiac death, severe bradycardic events as well as electromechanical dissociation may also occur due to advanced atherosclerosis [75]. Limited outcome data exist for implantable cardioverter-defibrillator therapy (ICD) in heart transplant recipients. ICD therapy has been reported to effectively terminate ventricular arrhythmias in transplanted patients with severe left ventricular dysfunction, severe allograft https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 8/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate vasculopathy, or history of cardiac arrest [76]. The effect of ICD therapy on long-term survival and quality of life in this population is not known. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Heart transplantation (Beyond the Basics)") SUMMARY While most arrhythmias after orthotopic heart transplantation are benign, there are several clinical associations with which the physician must be familiar: Early postoperative bradyarrhythmias due to sinus node dysfunction (SND) are probably caused by surgical trauma to the sinoatrial node or its blood supply and can partly be avoided using a bicaval anastomosis technique. (See 'Sinus node dysfunction' above.) Atropine is not an effective treatment for bradycardia when vagal innervation is absent; intravenous isoproterenol is suggested in the unlikely event that emergency treatment of https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 9/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate bradycardia is needed in the heart transplant patient without pacemaker wires in place. (See 'Treatment of sinus bradycardia' above.) Sustained atrial flutter and fibrillation are commonly associated with allograft rejection. Thus, the presence of these arrhythmias should prompt a search for acute rejection by endomyocardial biopsy. Empiric steroid therapy should be considered in such patients prior to return of the biopsy results. Adenosine should not be used to try to elucidate the mechanism of supraventricular tachyarrhythmias since it can result in transient, but significant, bradyarrhythmias. (See 'Atrial fibrillation or flutter' above and "Heart transplantation in adults: Treatment of acute allograft rejection".) Complex ventricular ectopy or atrioventricular block may be caused by either acute rejection or severe cardiac allograft vasculopathy. Affected patients should undergo endomyocardial biopsy followed, if rejection is not present, by coronary angiography to diagnose cardiac allograft vasculopathy. (See 'Ventricular arrhythmias' above and 'Conduction disturbances' above and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Insertion of a permanent pacemaker should be considered in patients with significant bradyarrhythmias, either from SND or high grade atrioventricular (AV) block, that are associated with decreased cardiac output and occur in the absence of acute rejection. (See 'Treatment of sinus bradycardia' above and 'Conduction disturbances' above.) Patients with frequent and symptomatic supraventricular tachycardia may be treated with radiofrequency catheter ablation. (See 'Supraventricular tachycardias' above.) Standard recommendations for ICD therapy apply to cardiac transplant recipients. Antiarrhythmic drug therapy is based on safety, tolerability, and clinical experience as limited published evidence is available for these drugs in cardiac transplant recipients. (See 'Ventricular arrhythmias' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. 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