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Arrhythmia after heart transplantation

Little is known about the incidence, risk factors and treatment of post-heart transplant arrhythmias. A variety of arrhythmias can occur after a heart transplantation (HTx). In all cases, endomyocardial biopsies and coronary angiographies need to be performed. The denervation of a transplanted heart, the use of immunosuppressant drugs, the risk of allograft rejection and vasculopathy change the incidence, prognosis and treatment of arrhythmias and the mechanisms of sudden cardiac death in these patients. The preoperative condition of recipients and donors is a risk factor for arrhythmia development. Arrhythmia management includes correction of risk factors and specific therapy for the arrhythmia itself.

Arrhythmias, General
CV Surgery - Transplantation


Keywords: arrhythmia, heart transplantation, atrial fibrillation, rejection, cardiac allograft vasculopathy

 

Background

Orthotopic heart transplantation (HTx) is the most effective long-term therapy for end-stage heart disease, with implantable left ventricular assist devices as an alternative for selected patients [1]. According to the International Society for Heart and Lung Transplantation (ISHLT), every year the number of HTxs increases [2]. As surgical techniques and immunosuppressive regimens have been refined, short-term mortality caused by sepsis has decreased, while morbidity caused by repeated rejection episodes and cardiac allograft vasculopathy (CAV) has increased and is often manifested by arrhythmias [1].

Hearts selected for HTx should be in good condition and generally beat in sinus rhythm (SR) [3]. Prolonged graft ischaemia time can predispose to conduction system injury in the early and late post-heart transplant periods. Perioperative ischaemic damage and subsequent endocardial fibrosis probably play a mechanistic role in many cases. Patients with prolonged graft ischaemia (>4 hours) are classified as high-risk and have greater 30-day and one-year mortality rates [4,5]. The risk of chronic rejection secondary to enhanced activation of the graft vessel endothelium may also be increased when myocardial preservation is not adequate [3,6].

The donor heart is completely denervated after transplantation. It should also be taken into account that the lack of parasympathetic activity is associated with the fact that after HTx most patients have a higher than average resting heart rate (HR) and significantly reduced heart rate variability [6]. Over time, both sympathetic and parasympathetic reinnervation will occur, but the degree of reinnervation is incomplete, non-uniform, variable between patients, and heterogeneous within the same patient [7,8]. Transection of the autonomic nerve fibres during HTx results in parasympathetic denervation and loss of the suppression of the sinoatrial (SA) node, leading to a persistent increase in resting HR. The sympathetic denervation contributes to a delay in exercise or stress-induced augmentation of SA node automaticity, resulting in diminished maximal HR response with exercise, which is primarily dependent on an increase in plasma catecholamine concentration [9,10,11].

Epidemiology, aetiology and triggers

A variety of arrhythmias can occur after HTx. The main underlying mechanisms of arrhythmias in a transplanted heart are due to surgery, rejection or CAV, the recipient’s prior drug exposure or from the transplanted heart itself [1,3]. Following the initial course after the HTx procedure, coronary artery disease (CAD) and CAV can cause arrhythmias [3].

Macroreentrant atrial tachycardia (AT)

Macroreentrant atrial tachycardia (AT) occurs mostly in the upper right atrium, around the native and donor suture line. The surgical scars at atrial suture lines can create areas of slower conduction. In the study of Hamon et al, these were successfully targeted in all ablations [1]. Recipient-to-donor atrial conduction tachycardia also usually involved the right atrial anastomosis. In these cases, ablations were successfully performed at the site of the earliest donor atrial activation on the suture line and the recipients’ atria were not targeted. Further, recipient tachycardia or atrial rhythm with exit block to the donor atrium can challenge physicians with complex electrocardiograms (ECGs) showing dual atrial tachycardia, pseudo-atrioventricular (AV) block or a pseudo-atrial tachycardia with atrial waves of two different morphologies (one from the donor and one from the recipient) [1].

AV and AV nodal reentrant tachycardia with successful ablation of the accessory or slow AV pathways

Sometimes arrhythmias can come with a transplanted heart, even if the donor never experienced any tachycardias or arrhythmias; changes in autonomic tone affecting the substrate are likely to be a mechanism of tachycardias in the recipient patient [1].

In the study by Vaseghi et al, the most common post-heart transplant arrhythmia was atrial flutter (9%) and persistent or paroxysmal atrial fibrillation (AF; 7%); 57% of AF occurred in the perioperative period [12]. Bicaval anastomosis might reduce scar-related AT, but AV valve isthmus-dependent atrial flutter can still occur in these patients [12]. AF is extremely rare in stable patients in the long term after HTx; when it does occur, late AF can be due to acute or chronic rejection, CAV or sepsis [1]. In fact, AT is an uncommon finding after HTx compared with other surgery, and is highly associated with acute rejection [1].

In addition, the majority of supraventricular tachycardias (SVTs) in stable heart transplant patients can be attributed to AT (flutter and scar reentry) [12]. An important cause of arrhythmias after HTx is a possible episode of rejection, which often manifests in supraventricular form [3].

Bradyarrhythmias occur in 8-23% of patients after orthotopic heart transplantation (OHT) depending on the case series. In most cases, sinus node dysfunction is the main complication; however, AV block may also occur [1]. Preoperative use of amiodarone in the recipient patient may also result in post-transplant bradycardia [1]. In patients with late onset symptomatic bradycardia, rejection and transplant coronary artery disease (TCAD) or CAV should be excluded [1,3,6].

Frequent arrhythmias during the initial time period after an HTx operation are bradycardiac sinus, AV node regulated or rhythms with supraventricular origin [3]. AV node dysfunction has similar multiple possible aetiologies in patients after HTx and is most frequent in the late period after HTx [1].

However, arrhythmias in late post-HTx follow-up are associated with worse outcomes due to acute rejection, left ventricle (LV) dysfunction, and sudden cardiac death (SCD). From retrospective studies, the mode of SCD manifestation in the vast majority of heart transplanted patients appears to be pulseless electrical activity (PEA) as opposed to ventricle fibrillation (VFib) [6].

Sudden cardiac death

Insights into SCD in heart transplant recipients came from the retrospective study by Vaseghi et al including 628 patients, with 194 deaths, including 116 with a determined cause. In this cohort, one third died from SCD, and the terminal rhythm was asystole in 34%, followed by PEA in 20% and VFib in only 10% (unknown in 36%). Almost two thirds of SCDs were induced by acute ischaemia. This subgroup yielded even more unexpected data since 50% died from asystole, 44% from PEA and only 6% (one patient) from VFib [12].

Most SCD in heart transplant patients is a consequence of TCAD or CAV, with mainly asystolic presentation and almost never VFib in patients with moderately depressed or preserved left ventricular ejection fraction (LVEF) [1].

Heart rate variability and re-innervation

It has already been reported that heart rate variability (HRV) of patients after HTx is extremely abnormal compared to normal individuals [13]. Therefore, the HRV of patients after HTx should be closer to patients with various types of heart disease and less like people without disease [13]. The observed changes in HRV during long-term follow-up after HTx are compatible with partial re-innervation of the cardiac sinus node, as has been suggested by cross-sectional studies [14].

Most studies have confirmed complete denervation within the first 6-12 months post transplant [14,15,16]. Once initiated, sympathetic re-innervation is progressive, and increases even late after transplantation, up to 15 years after surgery. However, the re-innervation process remains incomplete and regionally limited [15].

Exercise capacity and the maximal heart rate response to exercise are lower in recipients after HTx than in normal controls due to the absence of atrial and SA node innervation. Typically, the HR continues to rise after cessation of exercise as a result of delayed humoral catecholamine release and then returns slowly to resting values [15]. Transplant recipients with evidence of restoration of sympathetic innervation have better exercise performance compared to denervated recipients due to better chronotropic and inotropic response [15,16].

Prophylaxis and treatment

The prevention of mortality and SCD in post-heart transplant patients revolves around prevention of progressive CAV and early detection and treatment of rejection [3,6]. Subsequent to the initial course after an HTx operation, CAV can cause arrhythmias of all kinds. The post-HTx effects of some antiarrhythmic substances such as amiodarone administered preoperatively are at present under discussion as possibly being associated with an increased risk of mortality [3].

HR reduction with ivabradine is effective and potentially better tolerated than beta-blocker therapy after HTx. Although the prognostic role of HR after HTx is unknown, ivabradine may offer relevant symptomatic benefit, especially in cases of beta-blocker intolerance, and possibly due to exclusive modulation of heart rate without major systemic effects [17]. After HTx, the complex interaction of rejection, infection, inflammation, and mechanical stress caused by fibrosis or hypertrophy may render HR reduction prognostically beneficial [17].

In all post-heart transplant periods, permanent pacing is indicated for persistent symptomatic bradycardia [1]. Temporary cardiac pacing can be used during early-term follow-up in the intensive care unit (ICU); however, after two to three weeks post heart transplant it must be switched to a permanent one [1]. In addition, there are no specific guidelines regarding when to implant a cardioverter defibrillator (ICD).

Also, catheter ablation can be effective in the management of SVTs or ventricular extrasystoles (VES) [12] but not in cases where arrhythmias have been associated with a rejection or CAV.

Conclusions and future directions

Tolerability as well as the possible advantageous effects on the heart transplant population will have to be studied in patients with reduced LV function or severe restrictive physiology (e.g., due to gross hypertrophy); trials of ivabradine in systolic heart failure are currently underway [17]. In heart transplant recipients presenting with heart failure, systolic LV function is frequently preserved and coronary angiography is frequently abnormal, though it may also be normal or near normal. During follow-up, the main feature of these patients is a high mortality rate after heart failure diagnosis [18].

As survival after HTx continues to improve, enhanced management of post-transplantation arrhythmias has become important for reduction of morbidity. Arrhythmias can also serve as markers of otherwise unrecognised pathologies in the transplanted heart, such as rejection or CAV. Therapeutic electrophysiological procedures, such as pacemaker implantation and radiofrequency ablation, can be effective. With better postoperative care and reduction in the number of rejection episodes, the incidence of some arrhythmias, such as AF, can be decreased [6,19].

Pending randomised trials, any evidence of bradycardia or conduction disease merits very careful patient evaluation and consideration for either a pacemaker or an ICD [1]. In addition, specific guidelines with indications for ICD implantation must be developed.

References


  1. Hamon D, Taleski J, Vaseghi M, Shivkumar K, Boyle NG. Arrhythmias in the heart transplant patient. Arrhythm Elctrophysiol Rev. 2014;3:149-55. 
  2. Khush KK, Cherikh WS, Chambers DC, Goldfarb S, Hayes D Jr, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Stehlik J; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplantation Registry of the International Society for Heart and Lung Transplantion: Thirty-Fifth Adult Heart Transplantation Report-2018; Focus Theme: Multiorgan Transplantation. J Heart Lung Transplant. 2018;37:1155-1168. 
  3. Baretti R, Debus B, Lin BS, Weng YG, Pasic M, Hübler M, Grauhan O, Knosalla C, Dandel M, Kemper D, Hiemann N, Lehmkuhl HB, Hetzer R. Arrhythmia post heart transplantation. Applied Cardiopulmonary Pathophysiology. 2011;15:256-71. 
  4. Russo MJ, Chen JM, Sorabella RA, Martens TP, Garrido M, Davies RR, George I, Cheema FH, Mosca RS, Mital S, Ascheim DD, Argenziano M, Stewart AS, Oz MC, Naka Y. The effect of ischemic time on survival after heart transplantation varies by donor age: an analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg. 2007;133:554-9. 
  5. Christie JD, Edwards LB, Kucheryavaya AY, Aurora P, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report--2010. J Heart Lung Transplant. 2010;29:1104-18. 
  6. Thajudeen A, Stecker EC, Shehata M, Patel J, Wang X, McAnulty JH Jr, Kobashigawa J, Chugh SS. Arrhythmias After Heart Transplantation: Mechanisms and Management. J Am Heart Assoc. 2012;1:e001461. 
  7. Kim DT, Luthringer DJ, Lai AC, Suh G, Czer L, Chen LS, Chen PS, Fishbein MC. Sympathetic nerve sprouting after orthotopic heart transplantation. J Heart Lung Transplant. 2004;23:1349-58. 
  8. Uberfuhr P, Frey AW, Ziegler S, Reichart B, Schwaiger M. Sympathetic reinnervation of sinus node and left ventricle after heart transplantation in humans: regional differences assessed by heart rate variability and positron emission tomography. J Heart Lung Transplant. 2000;19:317-23. 
  9. Schwaiger M, Kalff V, Rosenspire K, Haka MS, Molina E, Hutchins GD, Deeb M, Wolfe E Jr, Wieland MD. Noninvasive evaluation of the sympathetic nervous system in the human heart by PET. Circulation. 1990;82:457-64. 
  10. Wilson RF, Johnson TH, Haidet GC, Kubo SH, Mianuelli M. Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation. Circulation. 2000;101:2727-33. 
  11. Cornelissen VA, Vanhaecke J, Aubert AE, Fagard RH. Heart rate variability after heart transplantation: a 10-year longitudinal follow-up study. J Cardiol. 2012;59:220-4. 
  12. Vaseghi M, Boyle NG, Kedia R, Patel JK, Cesario DA, Wiener I,  Kobashigawa JA, Shivkumar K. Supraventricular tachycardia after orthotopic cardiac transplantation. J Am Coll Cardiol. 2008;51:2241-9. 
  13. Lin YY, Li WA, Hsieh YC, Chang HH, Shih CC, Mei-Jy Jeng, Kuo CD. Effect of position on the residual heart rate variability in patients after orthotopic heart transplantation. J Chin Med Assoc. 2017;80:63-71. 
  14. Cornelissen VA, Vanhaecke J, Aubert AE, Fagard RH. Heart rate variability after heart transplantation: a 10-year longitudinal follow-up study. J Cardiol. 2012;59:220-4. 
  15. Grupper A, Gewirtz H, Kushwaha S. Reinnervation post-heart transplantation. Eur Heart J. 2018;39:1799-1806. 
  16. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic re-innervation on cardiac performance after heart transplantation. N Engl J Med. 2001;345:731-8. 
  17. Doesch AO, Celik S, Ehlermann P, Frankenstein L, Zehelein J, Koch A, Katus HA, Dengler TJ. Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine. Transplantation. 2007;84:988-96. 
  18. Ambrosi P, Kreitmann B, Riberi A, Lambert M, Pankert M, Habib G. Chronic heart failure in heart transplant recipients: Presenting features and outcome. Arch Cardiovasc Dis. 2016;109;254-9. 
  19. Vaseghi M, Lellouche N, Ritter H, Fonarow GC, Patel JK, Moriguchi J, Fishbein MC, Kobashigawa JA, Shivkumar K. Mode and mechanisms of death after orthotopic heart transplantation. Heart Rhythm. 2009;6:503-9. 

Notes to editor


Author:

Maria Simonenko, MD

Cardiologist-Transplantologist, Clinical Research Fellow in the Cardiopulmonary, Exercise Test Research Department, Almazov National Medical Research Centre, Saint-Petersburg, Russian Federation

 

Address for correspondence:

Dr. Maria Simonenko, 197341, Saint-Petersburg, Russian Federation,

Akkuratova street, 2, Heart Transplantation Department

E-mail: ladymaria.dr@gmail.com

 

Author disclosures:

The author has no conflicts of interest to declare.

 

 

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.