Keywords: arrhythmia, heart transplantation, atrial fibrillation, rejection, cardiac allograft vasculopathy
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 . According to the International Society for Heart and Lung Transplantation (ISHLT), every year the number of HTxs increases . 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 .
Hearts selected for HTx should be in good condition and generally beat in sinus rhythm (SR) . 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 . 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 .
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 . 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) .
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 .
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 . Bicaval anastomosis might reduce scar-related AT, but AV valve isthmus-dependent atrial flutter can still occur in these patients . 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 . In fact, AT is an uncommon finding after HTx compared with other surgery, and is highly associated with acute rejection .
In addition, the majority of supraventricular tachycardias (SVTs) in stable heart transplant patients can be attributed to AT (flutter and scar reentry) . An important cause of arrhythmias after HTx is a possible episode of rejection, which often manifests in supraventricular form .
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 . Preoperative use of amiodarone in the recipient patient may also result in post-transplant bradycardia . 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 . AV node dysfunction has similar multiple possible aetiologies in patients after HTx and is most frequent in the late period after HTx .
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) .
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 .
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) .
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 . Therefore, the HRV of patients after HTx should be closer to patients with various types of heart disease and less like people without disease . 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 .
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 .
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 . 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 .
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 . After HTx, the complex interaction of rejection, infection, inflammation, and mechanical stress caused by fibrosis or hypertrophy may render HR reduction prognostically beneficial .
In all post-heart transplant periods, permanent pacing is indicated for persistent symptomatic bradycardia . 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 . 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)  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 . 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 .
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 . In addition, specific guidelines with indications for ICD implantation must be developed.