Frequency, Risk Factors, and Clinical Outcomes of Late-Onset Atrial Flutter in Patients after Heart Transplantation

Aims: Atrial flutter (AFL) is a common late-onset complication after heart transplantation (HTX) and is associated with worse clinical outcomes. Methods: This study investigated the frequency, risk factors, and outcomes of late-onset post-transplant AFL. We analyzed 639 adult patients undergoing HTX at the Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis and type of late-onset post-transplant AFL (>90 days after HTX). Results: A total of 55 patients (8.6%) were diagnosed with late-onset post-transplant AFL, 30 had typical AFL (54.5%) and 25 had atypical AFL (45.5%). Patients with AFL were younger at HTX (p = 0.028), received more biatrial anastomosis (p = 0.001), and presented with moderate or severe tricuspid regurgitation (56.4%). Typical AFL was associated with graft rejection (p = 0.016), whereas atypical AFL was associated with coronary artery disease (p = 0.028) and stent implantation (p = 0.042). Patients with atypical AFL showed a higher all-cause 1-year mortality (p = 0.010) along with a higher rate of graft failure after diagnosis of AFL (p = 0.023). Recurrence of AFL was high (83.6%). Patients with catheter ablation after AFL recurrence had a higher 1-year freedom from AFL (p = 0.003). Conclusions: Patients with late-onset post-transplant AFL were younger at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation. Typical AFL was associated with graft rejection, whereas atypical AFL was associated with myocardial ischemia, graft failure, and mortality. Catheter ablation represents a viable option to avoid further episodes of late-onset AFL after HTX.

The traditional definition of AFL is based on 12-lead electrocardiogram (ECG) morphology and involves typical and atypical AFL [27]. Typical AFL is the most frequent cavotricuspid isthmus-dependent flutter cycling around the tricuspid anulus, with the cavotricuspid isthmus as the critical isthmus. The terms non-cavotricuspid isthmus-dependent macroreentrant tachycardia and atypical flutter are used synonymously and describe flutter waves in the ECG that are not suggestive of typical macro-reentrant circuits [27].
Given the risk profile of HTX recipients with late-onset AFL, these patients are at high risk for post-transplant morbidity and mortality. However, data on the clinical management of patients with late-onset post-transplant AFL are limited and even less is known about the differences between typical and atypical late-onset AFL after HTX. We therefore sought to investigate the risk factors, treatment, and clinical outcomes of late-onset AFL after HTX with special focus on typical and atypical AFL.

Patients
We performed this study in accordance with the ethical standards of the Declaration of Helsinki. The institutional review board (IRB) of Heidelberg University gave approval (ethics approval number: S-286/2015, Version 1.2, 28 July 2020). We obtained written informed consent from patients for their inclusion in the Heidelberg HTX Registry and the clinical and scientific use of their data. The ethics approval does not require additional consent for this observational study as only routine clinical data were used [11][12][13][14][15][16][17][18][19].
Our study included all adult patients (≥18 years) who received HTX at the Heidelberg Heart Center, Heidelberg, Germany, between 1989 and 2019, except for patients who had undergone repeat HTX. We initially stratified patients by diagnosis of late-onset post-transplant AFL (>90 days after HTX). Patients with late-onset post-transplant AFL were further divided into patients with typical and atypical AFL based on 12-lead ECG findings and electrophysiological study (EPS) data in case of performed ablation [27]. The traditional definition of AFL in general according to the 12-lead ECG morphology is as follows: continuous regular electrical activity, most commonly a saw-tooth pattern in contrast to focal atrial tachycardia, with isoelectric lines in between P-waves. [27].

Follow-Up
Patient follow-up was performed in accordance with the Heidelberg Heart Center's routine clinical protocol. After the initial hospital stay following HTX, patients were seen monthly as outpatients in the HTX clinic during the first six post-transplant months, then bimonthly until the end of the first year after HTX, and approximately three to four times per year thereafter (with additional visits on demand) [11][12][13][14][15][16][17][18][19].
Routine follow-up included medical history, physical examination, systolic and diastolic blood pressure measurement, blood and laboratory tests including immunosuppressive drug monitoring, resting 12-lead ECG, echocardiography, endomyocardial biopsy, annual chest X-ray as well as annual 24-h Holter monitoring. We were able to obtain complete follow-up data after HTX from all patients as no patient was lost to follow-up. In addition, we could record all causes of death within one year after diagnosis of late-onset AFL after HTX [11][12][13][14][15][16][17][18][19].

Post-Transplant Medications
Post-transplant medications including immunosuppressive drug therapy were administered as per the Heidelberg Heart Center's standard of care. Perioperatively, patients received an anti-thymocyte globulin-based immunosuppression induction therapy. Cyclosporine A and azathioprine were applied as the initial immunosuppression until 2001. Mycophenolate mofetil consequently replaced azathioprine from 2001 onward, and tacrolimus subsequently replaced cyclosporine A since 2006. Steroids were tapered incrementally during the initial post-transplant months and were discontinued six months after HTX (unless clinically needed) [11][12][13][14][15][16][17][18][19].

Statistical Analysis
The primary outcome of this study was 1-year mortality after diagnosis of late-onset post-transplant AFL, which was further assessed by stratification into patients with typical and atypical late-onset post-transplant AFL. Causes of death within one year after diagnosis of late-onset post-transplant AFL were categorized into the following groups: graft failure, acute rejection, infection/sepsis, malignancy, and thromboembolic event/bleeding [11][12][13][14][15][16][17][18][19].
Secondary outcomes included analysis of clinical findings, risks factors and treatment of patients with late-onset AFL after HTX. Our analysis comprised multiple univariate analyses in order to search for intergroup differences between patients with and without diagnosis of late-onset AFL after HTX as well as between patients with typical and atypical late-onset AFL after HTX. Parameters included recipient data, recipient previous openheart surgery, recipient principal diagnosis for HTX, donor data, transplant sex mismatch, perioperative data, immunosuppressive drug therapy, and post-transplant concomitant medications [11][12][13][14][15][16][17][18][19].
Patients with late-onset AFL after HTX were further analyzed with regard to clinical presentation and findings, echocardiographic features, and acute graft rejection (diagnosed ± 7 days at the time of AFL), as well as treatment modalities. Given the long study period of more than 30 years, we performed a sensitivity analysis to test the robustness of our results and to examine a possible era effect using a subgroup of patients with tacrolimus and mycophenolate mofetil, since the immunosuppressive drug regimen was changed from 2006 onward [11][12][13][14][15][16][17][18][19].
Data were analyzed using SAS (Version 9.4, SAS Institute, Cary, NC, USA) and shown as mean ± standard deviation (SD), median with quartiles (Q), or as count (n) with percentage (%). For measures of association, difference of mean or hazard ratio (HR) with 95% confidence interval (CI) were applied. Depending on the variable type and question, we used Student's t-test, Mann-Whitney U-test, analysis of variance (ANOVA), Kruskal-Wallis test, chi-squared test, or Fisher's exact test, as appropriate. The Kaplan-Meier estimator was used to graphically compare 1-year survival after diagnosis of late-onset post-transplant AFL in patients with typical and atypical AFL as well as to analyze 1-year freedom from further episodes of late-onset AFL after HTX between patients with and without catheter ablation after recurrence of late-onset post-transplant AFL. A p-value of <0.050 was considered statistically significant [11][12][13][14][15][16][17][18][19].

Demographics of Patients with and without Late-Onset Post-Transplant Atrial Flutter
Out of 639 included HTX recipients, 55 patients (8.6%) were diagnosed with lateonset post-transplant AFL. Of these, 30  Analysis of demographics between patients with typical and atypical late-onset AFL after HTX showed that typical AFL was more present in male HTX recipients (86.7% versus 64.0%; p = 0.049), while atypical AFL was associated with a significantly higher percentage of arterial hypertension (68.0% versus 40.0%; p = 0.038). Demographics stratified by typical and atypical late-onset AFL after HTX are presented in Table 2.

Medications after Heart Transplantation
In terms of the immunosuppressive drug therapy, we found no statistically significant differences between patients with and without diagnosis of late-onset AFL after HTX concerning the use of cyclosporine A, tacrolimus, azathioprine, or mycophenolate mofetil (all p ≥ 0.050). We also observed no statistically significant differences between patients with and without diagnosis of late-onset AFL after HTX regarding the administration of acetylsalicylic acid, beta blockers, ivabradine, calcium channel blockers, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, or statins (all p ≥ 0.050). Medications of study participants are given in Table 3. ACE inhibitor = angiotensin-converting-enzyme inhibitor; AFL = atrial flutter; ARB = angiotensin II receptor blocker; ASA = acetylsalicylic acid; CI = confidence interval; HTX = heart transplantation; n = number; n. a. = not applicable; † = gastric protection defined as proton pump inhibitor (PPI) or histamine receptor (H2) blocker.
Likewise, there were no statistically significant differences between patients with typical and atypical late-onset AFL after HTX concerning immunosuppressive drugs or concomitant medications (all p ≥ 0.050). Medications stratified by typical and atypical late-onset AFL after HTX are shown in Table 4. ACE inhibitor = angiotensin-converting-enzyme inhibitor; AFL = atrial flutter; ARB = angiotensin II receptor blocker; ASA = acetylsalicylic acid; CI = confidence interval; HTX = heart transplantation; n = number; n. a. = not applicable; † = gastric protection defined as proton pump inhibitor (PPI) or histamine receptor (H2) blocker.

Echocardiographic Features of Patients with Late-Onset Post-Transplant Atrial Flutter
Assessment of echocardiographic features showed that HTX recipients with late-onset post-transplant AFL had a high percentage of an enlarged right atrial (81.8%) and right ventricular diameter (70.9%) along with an elevated rate of reduced right ventricular function in more than half of all patients (52.7%). Comparison between patients with typical and atypical late-onset AFL after HTX indicated a higher rate of impaired left-sided heart function in patients with atypical late-onset AFL after HTX. They had a higher rate of a reduced left ventricular function ( Analysis of diastolic parameters showed that patients with atypical late-onset AFL after HTX had a higher early diastolic mitral inflow peak velocity (E) to late diastolic mitral inflow peak velocity (A) ratio (E/A; 3.1 ± 1.0 versus 2.3 ± 0.7; p = 0.002), a higher early diastolic mitral inflow peak velocity (E) to early diastolic mitral annular velocity (e ) ratio (E/e ; 15.1 ± 4.7 versus 7.7 ± 3.4; p < 0.001), a lower deceleration time (DT) of the early diastolic mitral inflow peak (E) (DT-E; 153.4 ± 27.6 ms versus 201.7 ± 26.8 ms; p < 0.001), a higher systolic pulmonary artery pressure (systolic PAP; 39.6 ± 10.2 mmHg versus 32.6 ± 9.9 mmHg; p = 0.013), a higher right atrial pressure (RAP; 12.2 ± 6.0 mmHg versus 8.2 ± 4.3 mmHg; p = 0.007), and a more dilated inferior vena cava (IVC; 23.6 ± 6.0 mm versus 19.7 ± 5.0 mm; p = 0.013). Echocardiographic features of patients with late-onset AFL after HTX are given in Table 6.

Treatment of Patients with Late-Onset Post-Transplant Atrial Flutter
At the initial occurrence of late-onset AFL after HTX, the majority of patients received either electrical (39 of 55 [70.9%]) or pharmacological cardioversion (9 of 55 [16.4%]) as treatment.
Patients with typical AFL received significantly more often electrical cardioversion (86.7% versus 52.0%; p = 0.005), while patients with atypical AFL received significantly more often pharmacological cardioversion (28.0% versus 6.7%; p = 0.033). No patient received catheter ablation at the initial occurrence of late-onset AFL after HTX, and spontaneous conversion of AFL only happened in a minority of patients (7 of 55 [12.7%]). Most patients with late-onset AFL after HTX had recurrence of AFL (46 of 55 [83.6%]). Preferred choice of treatment for patients with recurrence of late-onset AFL after HTX was catheter ablation which was performed in 20 patients (13 patients with typical AFL and 7 patients with atypical AFL; p = 0.239). By contrast, 15 patients received electrical cardioversion (12 patients with typical AFL and 3 patients with atypical AFL; p = 0.020) and 7 patients received pharmacological cardioversion (1 patient with typical AFL and 6 patients with atypical AFL; p = 0.022).
Comparison between patients with and without catheter ablation after recurrence of late-onset post-transplant AFL showed a significantly lower 1-year rate of further episodes of post-transplant AFL in patients with catheter ablation (p = 0.003). The Kaplan-Meier estimator of 1-year freedom from further episodes of post-transplant AFL stratified by patients with and without catheter ablation after recurrence of late-onset post-transplant AFL is presented in Figure 1. Further episodes of late-onset AFL after HTX occurred in about one-third of all patients (19 of 55 [34.5%]). Of these, 7 patients received pharmacological cardioversion (1 patient with typical AFL and 6 patients with atypical AFL; p = 0.022), 5 patients received electrical cardioversion (4 patients with typical AFL and 1 patient with atypical AFL; p = 0.231), 2 patients received catheter ablation (2 patients with typical AFL and 0 patients with atypical AFL; p = 0.188), and 2 further patients received repeat catheter ablation (1 patient with typical AFL and 1 patient with atypical AFL; p = 0.895). Treatment of patients with late-onset AFL after HTX is summarized in Table 7.

Sensitivity Analysis
Given the long study period, we performed a sensitivity analysis with a subgroup of HTX recipients who received tacrolimus and mycophenolate mofetil as immunosuppressive drug therapy [292 of 639 HTX recipients (45.7%)] in order to investigate a possible era effect and to examine the robustness of our results. This analysis showed similar findings supporting the robustness of our results and reducing the likelihood of a potential era effect.

Frequency and Risk Factors of Late-Onset Post-Transplant Atrial Flutter
Late-onset post-transplant AFL is a common complication late after HTX and plays an important role in the clinical management of HTX recipients [20]. Previous studies reported late-onset post-transplant AFL rates ranging from 8.0% to 11.5% [25,26,28,29]. Pavri and colleagues [28] published a late-onset post-transplant AFL rate of 8.0% (7 of 88) and Anselmino and colleagues [29] found a late-onset post-transplant AFL rate of 11.5% (42 of 364). This is in line with our late-onset post-transplant AFL rate of 8.6% (55 of 639). Regarding risk factors, the use of biatrial anastomosis has been associated with late-onset post-transplant AFL [20,22,23]. In HTX recipients with biatrial anastomosis, both donor atria are joined with most of the recipient atria resulting in enlarged atrial cavities with disruption of atrial anatomy and two long atrial anastomoses with plenty of potentially proarrhythmic scar tissue and substrate for a macro-reentry [17,[20][21][22][23][24][25][26]. In addition, there is also a higher rate of moderate to severe tricuspid regurgitation which has also been linked to late-onset post-transplant AFL [20,22,23,29]. Likewise, we observed a higher percentage of biatrial anastomosis and moderate to severe tricuspid regurgitation in patients with late-onset post-transplant AFL.
Another important finding of this study is the fact that patients with late-onset posttransplant AFL had a younger recipient age at the time of HTX. As the development of late-onset post-transplant AFL takes many years, older HTX recipients may not survive for such a long period and long-term survivors after HTX have a reported younger recipient age [24,25,29,30]. The median interval from HTX to the initial diagnosis of late-onset posttransplant AFL was around nine years in our study. Furthermore, lower HTX recipient age has been associated with graft rejection which in turn has been linked to late-onset post-transplant AFL [20][21][22][23][24][25]31,32]. Younger HTX recipients have a stronger immune system with increased alloreactivity, but adherence to prescribed medications and recommended lifestyle habits are less strict [31][32][33]. In this light, the above-mentioned risk factors acutely emphasize the aspects of time, altered anatomy, and proarrhythmic substrate in the development of late-onset post-transplant AFL.

Clinical Findings of Typical and Atypical Late-Onset Post-Transplant Atrial Flutter
To our knowledge, this is the largest study of HTX recipients with in-depth data analysis between patients with typical and atypical late-onset post-transplant AFL. Out of 55 HTX recipients with late-onset post-transplant AFL, 30 patients had typical AFL (54.5%) and 25 patients had atypical AFL (45.5%). Typical AFL was more common in male HTX recipients which is also the case in the general population [34,35]. Patients with atypical AFL showed a higher percentage of arterial hypertension, reduced right and left ventricular function (systolic, diastolic, and longitudinal function), as well as mitral regurgitation which may be the result of chronic changes and underlying cardiac allograft vasculopathy [20][21][22][23][24][25]. This is in line with our findings that HTX recipients with atypical AFL had a significantly higher percentage of coronary artery disease with requirement for coronary stent implantation and a higher all-cause 1-year mortality along with a higher rate of graft failure after diagnosis of AFL. Matters are complicated further by the fact that more than a quarter of HTX recipients with atypical AFL were asymptomatic on presentation, and asymptomatic AFL can remain unnoticed for weeks or even months until it is incidentally found on routine resting 12-lead ECG or on routine 24-h Holter monitoring [34,35].
In contrast, most HTX recipients with typical AFL were symptomatic in our study. The majority of these patients had palpitations which might result from a significantly higher percentage of AFL with 2:1 atrioventricular conduction in comparison to patients with atypical AFL. Palpitations as a main symptom of HTX recipients with typical AFL were also reported in smaller studies with AFL after HTX [24,36,37]. Furthermore, HTX recipients with typical AFL had a significantly higher percentage of acute graft rejection. This may explain why previous studies were inconclusive about an association between graft rejection and post-transplant AFL in general [20][21][22][23][24][25][26]. Given these differences between patients with typical and atypical late-onset post-transplant AFL, we particularly recommend myocardial biopsy to exclude acute graft rejection in HTX recipients with typical AFL and cardiac catheterization to rule out presence of acute myocardial ischemia in HTX recipients with atypical AFL.
Rodríguez-Entem and colleagues [24] performed successful catheter ablation of the cavotricuspid isthmus in 12 of 13 HTX recipients (92.3%) with post-transplant AFL. They observed a recurrence of post-transplant AFL in 3 of 12 HTX recipients (25.0%) who underwent repeat catheter ablation during a mean follow-up of 24 ± 17 months [24]. Vaseghi and colleagues [26] performed catheter ablation of the cavotricuspid isthmus in 14 HTX recipients with typical post-transplant AFL and reported recurrence of AFL in two patients (14.3%) who required a second catheter ablation [26]. Similar results were reported by Mouhoub and colleagues [40] who performed catheter ablation of the cavotricuspid isthmus in 28 of 30 HTX recipients (93.3%) with typical post-transplant AFL as well as catheter ablation of atypical post-transplant AFL in 2 of 30 HTX recipients (6.7%). They reported a primary catheter ablation success in 28 of 30 HTX recipients (93.3%) [40]. The largest study on catheter ablation of post-transplant AFL so far was published by Taylor and colleagues [25] who performed catheter ablation of the cavotricuspid isthmus in 26 of 32 HTX recipients (81.2%) with typical post-transplant AFL as well as catheter ablation of atypical post-transplant AFL in 6 of 32 HTX recipients (18.8%). In this case, 8 of the 32 patients (25.0%) underwent repeat catheter ablation [25].
In our study, 20 HTX recipients with recurrence of late-onset post-transplant AFL received catheter ablation (13 patients with typical AFL and 7 patients with atypical AFL). Only 2 of these 20 HTX recipients (10.0%) had a further episode of post-transplant AFL within one year after catheter ablation. In comparison to HTX recipients without catheter ablation after recurrence of late-onset post-transplant AFL, HTX recipients with catheter ablation after recurrence of late-onset post-transplant AFL showed a significantly lower 1-year rate of further episodes of post-transplant AFL (p = 0.003). These findings are of high clinical relevance as there is a high risk of AFL recurrence in patients after HTX, and standard treatment of patients with AFL after HTX still consists of electrical or pharmacological cardioversion. Therefore, given the distinct cardiovascular risk profile of HTX recipients with late-onset post-transplant AFL, catheter ablation represents a viable option for HTX recipients in order to avoid further episodes of post-transplant AFL.

Study Limitations
The results of our study were derived from a large single-center registry (Heidelberg HTX Registry) including the highly detailed data of 639 patients who received HTX at the Heidelberg Heart Center. In awareness of the known limitations of such a study design, our findings should be interpreted carefully and within the context of the existing literature. However, we would like to emphasize that our study was comparable to multicenter studies in sample size and our patients received standardized treatment and follow-up, reducing the likelihood of selection bias and potential confounders [11][12][13][14][15][16][17][18][19].
Long-term follow-up is essential to detect late-onset post-transplant AFL. We therefore decided to analyze patients who received HTX at the Heidelberg Heart Center between 1989 and 2019 providing a minimum follow-up of two years after HTX. As a consequence of the long study period of more than 30 years, a possible era effect due to changes in surgical and medical care may have influenced our findings. In order to investigate a possible era effect, we performed a sensitivity analysis with HTX recipients who received tacrolimus and mycophenolate mofetil, since tacrolimus replaced cyclosporine A as the main immunosuppressive agent from 2006 onward. This analysis showed similar results supporting the robustness of our findings [11][12][13][14][15][16][17][18][19].
Assessment of late-onset post-transplant AFL was based upon all available source files including resting 12-lead ECGs, monitor-telemetry, 24-h Holter monitoring, and EPS data in the case of performed ablation. The type of AFL was diagnosed on 12-lead ECG criteria [27] but an atypical ECG pattern could not exclude CTI-dependent macro-reentrant tachycardia. As EPS was not performed in all patients with late-onset AFL after HTX, we cannot rule out that some patients with an ECG pattern of atypical AFL who did not undergo catheter ablation might have been misclassified. It is also possible that asymptomatic episodes of AFL could have been missed. However, as most HTX recipients with AFL were symptomatic and patients after HTX were routinely followed-up with resting 12-lead ECG and 24-h Holter monitoring, it is very unlikely that a significant number of HTX recipients with AFL were undetected. In addition, our findings should be interpreted as hypothesis-generating, especially in the context of risk factors for late-onset post-transplant AFL and mortality after HTX, because multiple factors can influence these outcomes. Furthermore, the long-term effects of catheter ablation in HTX recipients with AFL after HTX remain unknown and require further investigation, preferably in the form of large multicenter trials.

Conclusions
Post-transplant AFL is a common and clinically relevant cardiac arrhythmia late after HTX. About one out of ten HTX recipients suffered from it and the median interval from HTX until the initial diagnosis of late-onset post-transplant AFL was around nine years. Patients with late-onset post-transplant AFL had a lower recipient age at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation, all underlining the aspects of time, altered anatomy, and proarrhythmic substrate in the development of late-onset post-transplant AFL. Regarding the differences between typical and atypical AFL, typical AFL was associated with symptomatic palpitations and acute graft rejection, while atypical AFL was common in asymptomatic HTX recipients with coronary artery disease and requirement for coronary stent implantation. Impaired right-sided heart function was found in more than half of HTX recipients with late-onset post-transplant AFL, but a significant number of patients with atypical AFL also showed a reduced left-sided heart function and had a higher all-cause 1-year mortality along with a higher rate of graft failure after diagnosis of AFL. Initial standard treatment of patients with new-onset AFL after HTX mainly consists of electrical or pharmacological cardioversion, whereas catheter ablation is often only used in cases of recurrence. However, since most patients with late-onset AFL after HTX suffer from recurrence of AFL and the recurrence rate of AFL after catheter ablation is significantly lower, catheter ablation may not only represent a viable option for HTX recipients with recurrence of post-transplant AFL but also for HTX recipients with new-onset post-transplant AFL, especially in the light of the risk profile and vulnerability of these patients.

Informed Consent Statement:
We obtained written informed consent from patients for their inclusion in the Heidelberg HTX Registry and the clinical and scientific use of their data. The ethics approval does not require additional consent for this observational study as only routine clinical data were used.

Data Availability Statement:
The original contributions presented in this study are included in the article; further inquiries can be directed to the corresponding author.