Right Heart Structure and Function after Electrical Cardioversion for Atrial Fibrillation

Introduction: Atrial fibrillation (AF) adversely impacts right ventricular (RV) and right atrial (RA) structure and function. There are limited data on these changes after electrical cardioversion (ECV) and the relative contribution of heart rate to evaluate the immediate (1–2 h) and short-term (4–6 weeks) changes in right cardiac chamber dimensions and RV function after ECV in patients with persistent AF. Methods: Right cardiac chamber dimensions and RV function were measured in 64 patients using transthoracic echocardiography 1–2 h before, immediately after, and 4–6 weeks after ECV. Associations between changes in right-heart measures and rhythm status at follow-up were assessed using linear regression models. Results: For patients who remained in sinus rhythm 4–6 weeks after ECV (n = 48), median fractional area change (FAC) at baseline, immediately after ECV, and 4–6 weeks after ECV were 39 (Q1:35, Q3:42) %, 42 (Q1:39, Q3:46) %, 46 (Q1:43, Q3:49) % (p < 0.01); median tricuspid annular plane systolic excursion (TAPSE) values at the same time points were 18 (Q1:17, Q3:20) mm, 20 (Q1:18, Q3:23) mm, and 24 (Q1:22, Q3:26) mm (p < 0.01), respectively. There was no significant difference in RV end systolic area and RA volume index before and after ECV. However, RV end systolic area and RA volume index decreased significantly after 4–6 weeks from a median of 10 (Q1:8, Q3:13) cm2 to 8 (Q1:7, Q3:10) cm2 (p < 0.01), and from a median of 30 (Q1:24, Q3:36) mL/m2 to 24 (Q1:20, Q3:27) mL/m2 (p < 0.01). Changes in TAPSE were significantly associated with sinus rhythm at follow-up (p = 0.027), changes in FAC showed a strong trend to association with sinus rhythm (p = 0.053), and this was not true for RA measures (p = 0.64). Conclusions: Among AF patients who remained in sinus rhythm after ECV, RV function improved immediately after ECV with further improvement at 4–6 weeks following sinus rhythm restoration.


Introduction
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia worldwide and is associated with increased morbidity and mortality [1].The prevalence of AF has increased by a third in the global population in the last 20 years, a trend that is expected to continue in the future, resulting in a >60% increase in prevalence by 2050 [2].
While AF can be the consequence of heart failure with reduced ejection fraction, AF can in turn also lead to biventricular systolic dysfunction as well as structural changes including ventricular and atrial dilatation [3,4].Decreased diastolic filling, absence of active atrial contraction, and changes in the ultrastructure of the myocardium all contribute to reduced systolic function [5][6][7][8][9][10][11].These effects are pronounced in patients with poorly controlled ventricular rates and are referred to as tachycardia-induced cardiomyopathy (TIC) [12,13].Upon electrical cardioversion (ECV), at least some of the changes are reversible, with an acute improvement in left ventricular (LV) systolic function mainly attributable to the control of heart rate (HR) and a further improvement in subsequent weeks due to the reversal of TIC.The changes in ventricular function and atrial size have been well characterized for the left ventricle and atrium [14].For the right ventricle, studies have focused on the improvement in right ventricular (RV) systolic function after ECV [15][16][17].Also, published studies did not characterize the relative contributions of short-term changes in RV function induced by changes in HR mainly driven by an increased diastolic filling period versus long-term contributions of the recovery of right atrial (RA) contraction and reversal of TIC.The purpose of our study was therefore to characterize the contribution of shortterm change in HR versus reversal of TIC to recovery of RV function by echocardiographic assessment immediately and 4-6 weeks after an ECV.

Study Population
Study participants were from the GAPP-AF (gene expression patterns for the prediction of AF) study, a prospective study that enrolled 100 patients with persistent AF who were scheduled to undergo an elective ECV due to AF-related symptoms.Of these, 8 patients were excluded due to incomplete echocardiography data, and 28 patients were excluded due to insufficient image quality of the right heart chambers in the echocardiographic studies.All patients included were older than 18 years, had persistent AF, and were scheduled to undergo ECV according to current guidelines [18].Persistent AF was confirmed using standard 12-lead and 24-h Holter electrocardiogram (ECG) prior to ECV.Other exclusion criteria were acute heart failure or unstable coronary disease, untreated severe valvular disease, limiting active or chronic disease, and having a history of major heart surgery within 3 months prior to enrollment.Patients with insufficient anticoagulation, left atrial (LA) thrombi, or unsuccessful ECV are also excluded from the study.Patients with successful ECV and immediate relapse of AF remained in the study.

Baseline Measurements and Echocardiographic Studies
Baseline characteristics were collected using standardized case report forms.Three consecutive blood pressure measurements were obtained at baseline, and the mean of them was used.ECV was performed according to institutional standards.Transthoracic echocardiography was performed on iE33 (Philips Medical Systems, Andover, MA, USA) systems equipped with X5-1 transducers.Images were acquired immediately before, within 1-2 h after, and 4-6 weeks (follow-up) after ECV by experienced cardiologists.In patients who were in sinus rhythm at follow-up, at least 2 cardiac cycles were stored, and for those in AF, 3 to 5 cardiac cycles were stored.Off-line analyses were performed with a dedicated software package (Tomtec Imaging Systems, Unterschleissheim, Munich, Germany).RA and RV measurements, including RV fractional area change (FAC), RA volume, and RA volume index (RAVI), were derived from apical four-chamber views, and tricuspid annular plane systolic excursion (TAPSE) was measured according to guidelines [19].For patients in AF, measurements were averaged from all available heart beats (at least 3 cycles).

Outcome Assessment
For all patients, a follow-up visit was scheduled 4-6 weeks after ECV.Patients were advised to obtain ECG documentation every time they experienced AF-associated symptoms, such as palpitations or irregular heartbeat.Before the follow-up visit, all patients had another 24-h Holter ECG recording to document the actual HR state at the final follow-up visit.AF recurrence was defined as any AF episode lasting longer than 30 s on an ECG recording (either on the follow-up 24-h Holter ECG recording or any 12-lead ECG recording obtained during follow-up).

Statistical Analysis
The patients were stratified according to the AF recurrence status during follow-up.Continuous variables are expressed as median (interquartile range; IQR) and were compared using a Wilcoxon two-sample test.Categorical variables are expressed as numbers and percentages and were compared using Fisher's exact or χ 2 tests.χ 2 tests were applied when all theoretical numbers T ≥5 and total sample size n ≥ 40.Otherwise, Fisher exact tests were applied.
Linear regression models were constructed to analyze the effect of rhythm status after ECV on RV function (FAC and TAPSE) and RAVI with rhythm status as an independent variable and changes in FAC, TAPSE, or RAVI as dependent variables.Multivariable models were adjusted for age, sex, BMI (kg/m 2 ), history of AF (months), HR changes, history of heart failure, coronary heart disease, and hypertension.To evaluate the effect of changes in HR on RV function, a linear regression model was constructed using changes in HR as the independent variable and changes in RV function as the dependent variable.Statistical significance was defined as p < 0.05.All analyses were performed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, NY, USA).

Results
Of the 64 patients with persistent AF enrolled in the present study, 48 remained in sinus rhythm 4-6 weeks after ECV (sinus rhythm group), while 16 had recurrence of AF at follow-up (AF recurrence group).Baseline characteristics according to AF recurrence status are presented in Table 1.There were no statistically significant differences.Also, no changes in antiarrhythmic drug medication were observed.

Right Heart Structure and Function
Right heart function and volume parameters are presented in Table 2. Values for RV end diastolic area before ECV were larger than published normal values; values for TAPSE and FAC before ECV were lower than published normal values but not below published thresholds indicating overt systolic dysfunction [20].In patients who remained in sinus rhythm, both TAPSE and FAC significantly increased immediately after and 4-6 weeks after ECV.The immediate increase in FAC accounted for 50% of the total recovery in RV function; this was similar for TAPSE with an immediate increase that accounted for 40% of the total recovery.Patients who experienced a recurrence of AF did show a significant improvement of TAPSE and a small, nonsignificant improvement of FAC immediately after ECV, but both parameters significantly decreased during follow-up, which resulted in significantly worse TAPSE and FAC when compared to patients in sinus rhythm at follow-up (p < 0.01 for both comparisons).
RV end diastolic area numerically decreased in both groups of patients 4-6 weeks after ECV, but this was not statistically significant.In contrast, RV end systolic area decreased significantly at 4-6 weeks after ECV in patients in the sinus rhythm group.In patients in the AF recurrence group, RV end systolic area remained unchanged throughout the study.Maximum RA volume and RA parameters decreased significantly in the sinus rhythm group but remained unchanged in the AF recurrence group at follow-up.

Changes in Right Ventricular Function and Heart Rate according to Rhythm Status
Results of the multivariable regression analyses are shown in Table 3. Changes in FAC and TAPSE were significantly associated with sinus rhythm at follow-up, but this was not the case for RA volume index.Of note, there was no association between changes in HR and changes in FAC (R 2 = 0.002, β = −0.09,p = 0.8) and TAPSE (R 2 = 0.003, β = −0.3,p = 0.7) from baseline to follow-up in patients in the sinus rhythm group, and a weak, albeit significant correlation, when analyzing all 64 patients (FAC: R 2 = 0.13, p = 0.01; TAPSE: R 2 = 0.17, p = 0.04).

Discussion
In this study, we show that among patients who remain in sinus rhythm after ECV, there is (1) an immediate improvement in RV systolic function, (2) continuous recovery in RV systolic function during follow-up, and (3) this improvement was not associated with changes in HR after ECV.Rapid ventricular rate, decreased diastolic filling time, decreased preload due to loss of atrial contractility, irregular ventricular activation, and ultrastructural changes affecting myocyte function cause reduced ventricular function in patients with AF.It has been previously shown that ECV in patients with persistent AF results in an immediate improvement of the left ventricular ejection fraction followed by further improvement in the 4-6 weeks following ECV [14,20].
However, the right ventricle differs from the left ventricle in terms of its structure and function.This includes a more complex geometry, different myofiber architecture, higher compliance, and a longer diastolic filling period [21].The RV systolic function depends on an inward motion of the free wall due to contraction of obliquely oriented and circular myofibers in the superficial and middle layers, on motion of the tricuspid annular plane towards the apex due to contraction of longitudinally oriented subendocardial myofibers and traction on the insertion points of the RV wall in the left ventricular myocardium [21].Despite these anatomical and functional differences, our data show a time course of RV functional recovery that is similar to what has been observed for the LV [14,16] with a significant improvement immediately after ECV and a further improvement in the subsequent 4-6 weeks.Our results are in line with previous observations [15,16] in smaller studies without a control group composed of patients with recurrence of AF.Both TAPSE and FAC showed a similar improvement over time, indicating that longitudinal function (measured by TAPSE) and global function including both longitudinal and radial functions (measured by FAC) improved similarly.
In contrast to observations of LV function after ECV in the same study population [14], we found no association between changes in HR and changes in RV function.However, it has been shown that irregular cardiac myocyte activation negatively affects intracellular calcium handling and thus excitation-contraction coupling [22] independent of HR.Also, irregular ventricular activation in patients with AF has been shown to increase sympathetic nerve activity [23], which could further amplify myocyte dysfunction.Thus, contrary to the left ventricle, changes in HR may play a less important role, whereas regularization of HR may contribute to reversal of TIC and the improvement in RV function.
RV dimensions decreased over time after ECV; this was significant for RV end systolic area, whereas there was a trend for decreased RV end diastolic area.Thus, while there was a modest degree of RV reverse remodeling, an improvement in RV systolic function was mainly responsible for the changes in RV volumes.
While RV end diastolic area did not change significantly, we found a significant and large decrease in RA volume after ECV.These results expand similar findings from a previous study in which patients with heart failure with preserved ejection fraction (HFpEF) and sinus rhythm or prior AF had significantly lower RA volumes than patients with HFpEF and current AF [4].Both restoration of sinus rhythm as well as a decrease in RV-filling pressure may have contributed to the effect we observed, which was not immediate but rather developed over time with significant changes present at 4-6 weeks after ECV.
The strengths of this study are (1) the prospective observation of a number of well-characterized patients with persistent AF undergoing ECV at predefined and relevant time points, and (2) comparison to a group with relapse of AF after ECV.However, there are some limitations that need to be addressed.First, 31 patients included in the database could not be evaluated due to either incomplete imaging datasets or insufficient image quality.These 31 patients had a higher BMI and did more often have diabetes mellitus but did not differ in terms of other clinical characteristics from the 64 patients included in the present analysis (online suppl.Table 1; for all online suppl.material, see https://doi.org/10.1159/000531704).Second, TAPSE and FAC were measured as parameters of RV function.Tissue Doppler measurement of tricuspid annular systolic velocity, RV strain, or 3D echocardiography might have added information, but was not recorded in this prospective study.Finally, the time frame over which RV function and RA dimensions were observed may not have shown the full potential of recovery of right heart structures.

Conclusion
In patients who remain in sinus rhythm after ECV for AF, RV function improved, and RA volume decreased 4-6 weeks after the intervention.Unlike LV function, these changes were not associated with changes in HR.

Statement of Ethics
The study was conducted according to the Declaration of Helsinki and approved by the Local Ethics Committee, Ethikkommission Nordwest-und Zentralschweiz (EKNZ), approval number 342/09, date of approval February 1st, 2010.Written informed consent was obtained from all patients.

Table 2 .
Right-heart volumes at baseline and follow-up stratified by rhythm status at follow-up

Table 3 .
Association of change in echocardiographic parameters with rhythm status after cardioversion Estimated effect sizes were obtained from multivariate linear regression models with AF recurrence as the reference, rhythm status at follow-up was the dependent variable, and the change of echocardiographic parameter as the independent variable.*Adjusted for age (years), sex, BMI (kg/m 2 ), history of AF (months), heart rate changes, history of heart failure, coronary heart disease, and hypertension.