Atrial Remodeling Following Catheter Ablation for Atrial Fibrillation-Mediated Cardiomyopathy: Long-Term Follow-Up of CAMERA-MRI Study
New Research Paper
Central Illustration
Abstract
Objectives:
This study sought to determine the long-term right atrial (RA) electrical and structural changes in a subgroup from the CAMERA-MRI (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction-Magnetic Resonance Imaging) study.
Background:
Catheter ablation (CA) is successful in restoring ventricular function in patients with atrial fibrillation (AF) and otherwise unexplained cardiomyopathy, as demonstrated in the randomized study of CA versus rate control (CAMERA-MRI). It is unknown if this is associated with atrial remodeling.
Methods:
Detailed electroanatomical (EA) mapping of the RA using CARTO3 and a force sensing catheter was performed at initial CA and electively at least 12 months after CA in patients with >90% reduction in AF burden following ablation. Bipolar voltage, fractionation, and conduction velocity were collected in 4 segments together with echo and cardiac magnetic resonance imaging.
Results:
Fifteen patients (mean age 59.1 ± 6.8 years) underwent repeat RA EA mapping. At a mean follow-up of 23.4 ± 11.9 months, left ventricular (LV) ejection fraction improved from 33.6 ± 3.2% to 54.1 ± 3.2% (p = 0.001), RA area decreased from 28.4 ± 2.0 cm2 to 20.8 ± 1.2 cm2 (p < 0.001), and left atrial area decreased from 32.9 ± 2.3 cm2 to 26.8 ± 1.4 cm2 (p = 0.007). On EA mapping, RA bipolar voltage increased from 1.6 ± 0.1 mV to 1.9 ± 0.1 mV (p = 0.04). Tissue voltage increased across all regions, which achieved statistical significance at the posterior (p = 0.002) and septal (p = 0.01) segments. There was a significant decrease in complex fractionated electrograms from 21.7 ± 3.5% to 8.3 ± 1.8% (p = 0.002); however, no significant change occurred in global or regional conduction velocities (p = 0.5).
Conclusions:
Recovery of atrial electrical and structural changes was observed following restoration of sinus rhythm and recovery of LV function in patients who underwent CA for persistent AF and LV systolic dysfunction. The randomized CAMERA MRI study demonstrated significant improvement in LV systolic function with AF ablation compared with rate control. The present study demonstrated reverse electrical and structural atrial recovery in concert with recovery of LV systolic function at 2 years post-AF ablation. This may partially explain the long-term success of CA in patients with AF and otherwise unexplained cardiomyopathy.
Introduction
Atrial fibrillation (AF) and heart failure (HF) are modern epidemics in cardiovascular disease, and their combination is associated with increased morbidity and mortality (1–4). People with HF have more advanced atrial remodeling and fibrosis, with a consequential increase in recurrent arrhythmia and a poorer prognosis (5–8). Randomized pharmacological trials of rate control versus rhythm control strategies in AF and HF have not demonstrated a superiority of rhythm control. However, subgroup analysis has suggested sinus rhythm was associated with improved survival, but the benefits of sinus rhythm were negated by the limited efficacy and toxicity of antiarrhythmic medication (9).
Catheter ablation (CA) is successful in restoring ventricular function and reducing mortality in patients with AF and HF as demonstrated in randomized controlled studies (1,10). The CAMERA-MRI (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction−Magnetic Resonance Imaging) study randomized patients with persistent AF and otherwise unexplained left ventricular (LV) systolic dysfunction to CA versus medical rate control. There were substantial improvements in LV function and reductions in diffuse fibrosis on cardiac magnetic resonance (CMR) in concert with successful restoration of sinus rhythm confirmed on implantable recorder monitoring (11). However, the long-term effect on atrial electrical and structural function in this population has yet to be defined, which may have important implications for long-term clinical outcomes. We sought to determine if recovery of LV function with the restoration of sinus rhythm was associated with changes in atrial electrical and structural characteristics in a subgroup of patients who underwent CA as part of the CAMERA-MRI study.
Methods
Study population
All participants from the CAMERA-MRI study were screened for inclusion. Detailed baseline information about the study population was published previously (1). In summary, all participants who underwent CA that included pulmonary vein isolation, post-wall isolation, and baseline right atrial (RA) mapping (n = 24) at the time of CA were invited to participate. To determine the impact of restoration of sinus rhythm, a >90% reduction in AF burden was required for study inclusion. Participants were admitted for an electrophysiological (EP) study performed in the cardiac catheter laboratory under sedation. The study was approved by the Alfred Health Ethics Review Committee in Melbourne, Australia. All participants provided written informed consent to be in included in the study.
Study protocol
All participants were followed up for heart rate monitoring using pre-existing loop recorders, dual-chamber or biventricular defibrillators, serial electrocardiograms, or 24-h Holter monitors. In addition, transthoracic echocardiography and CMR were repeated as close to the time of their follow-up EP study as possible.
EP study and electroanatomical mapping
The approach to the EP study and electroanatomical (EA) mapping was previously described in detail (4,12). In summary, a RA map was created using a 4-mm irrigated ThermoCool SmartTouch contact force-sensing catheter (Biosense Webster, Diamond Bar, California) ablation catheter with the assistance of the CARTO 3 (Biosense Webster) system during proximal coronary sinus pacing at 600 ms (Central Illustration). An even distribution of at least 150 points was targeted across all atrial regions with the assistance of the The ConfiDENSE module (Biosense Webster, Inc.). EA RA maps were analyzed off-line, and only points with contact force of >5 grams were included in the analysis. Every individual point was manually annotated for local activation timings and checked for consistency. Analysis was performed at 200 mm/s sweep speed for complex fractionated electrograms (CFEs). CFE was defined as electrograms with ≥3 deflections of ≥50 ms duration and reviewed in a blinded fashion. The maximum difference in voltage between the highest and lowest amplitude deflection was taken as the bipolar voltage. Scar was defined as <0.05 mV, and low voltage was defined as <0.5 mV on bipolar voltage. Global and regional voltage was determined by the average voltage across the entire atria for global analysis or within each region for regional analysis. For the purpose of regional analysis, the RA was divided into 4 segments that consisted of the anterior, lateral, posterior, and septal segments as described previously (4). The 4 anatomical regions were divided into relatively equal sections of the RA. The anterior RA encompassed the atrial appendage, the posterior RA included the crista terminalis, the septum included the region bounded superiorly by the base of the superior vena cava to include the fossa ovalis, the atrioventricular nodal region, and ostium of the coronary sinus.
Electroanatomical Map of the RA at Baseline and Follow-Up
Baseline and follow-up bipolar voltage maps of right atrium (RA) demonstrating an increase in bipolar voltage and a decrease in fractionation in the posterior-septal segment(s). (A and B) Posterior-anterior projection with lateral rotation at baseline and (C and D) of the same view at follow-up. (A and C) Unadjusted automatic bipolar voltage. (B and D) Bipolar voltage maps adjusted to 0 to 0.5 to 1.0 mV. Low voltage is represented by red. Fractionated signals are marked with a turquoise arrow and circle. IVC = inferior vena cava; SVC = superior vena cava.
Conduction velocity
Conduction velocity was measured off-line using previously published methodology (4,12). In summary, the maps were analyzed with isochronal line settings of 5 ms. Local activation time (LAT) was manually annotated as per previous studies (13), based on bipolar and unipolar signals using the maximum negative slope (−dV/dT), and compared unipolar signals with simultaneous bipolar activity to exclude potential far-field signals. In the presence of fractionation, the dominant potential was annotated and ensured consistency with surrounding electrograms. Five pairs of points were taken in each of the 4 segments, and conduction was measured perpendicularly across the isochronal steps. Conduction velocity was then calculated by dividing the difference in LAT by the measured shortest distance, which was represented as meters per second. A scar filter of 0.05 mV was set, and these areas were not assigned an LAT.
Statistical analysis
Paired Student’s t-test was used to compare means from baseline to follow-up. Continuous variables of baseline demographics are expressed as mean ± SD. Results are expressed as mean ± SEM. Categorical variables were expressed as number and proportion. A p value <0.05 was considered significant. All statistical calculations were performed using SPSS 24 (IBM, Armonk, New York).
Results
Study population
Of the 66 participants with persistent AF in the CAMERA-MRI study, 33 participants underwent ablation. Twenty-four participants had baseline RA maps and were invited to participate in the follow-up study. Of these, 15 underwent and completed follow-up RA mapping, with 6 unwilling to proceed with elective EP study; 2 were considered medically unfit. There was 1 death.
Baseline characteristics of the study population are detailed in Table 1. The mean age was 59.1 ± 6.8 years, 93.3% were men with an average body mass index of 29.7 ± 4.5 kg/m2 and a CHA2DS2VASc score of 2.3 ± 1.1. This was a representative group of the entire CA cohort with no significant differences in baseline characteristics.
| Study Population (n = 15) | CAMERA-MRI Ablation Group (n = 33) | |
|---|---|---|
| Age, yrs | 59.1 ± 6.8 | 59.0 ± 11.0 |
| Male | 14 (93.3) | 31 (93.9) |
| CHA2DS2VASc score | 2.3 ± 1.1 | 2.4 ± 0.9 |
| Hypertension | 4 (26.7) | 13 (39) |
| Diabetes | 2 (13.3) | 4 (12) |
| BMI, kg/m2 | 29.7 ± 4.5 | 30.0 ± 7.5 |
| History of long-standing persistent AF | 10 (66.7) | 24 (72) |
| Ejection fraction, % (mean ± SEM) | 33.6 ± 3.2 | 31.8 ± 1.6 |
| RA area, cm2 | 28.4 ± 7.2 | 27.1 ± 6.3 |
| LA area, cm2 | 32.9 ± 8.2 | 30.5 ± 7.0 |
The average time to follow-up RA mapping after initial ablation was 23.4 ± 11.9 months. Cardiac monitoring demonstrated an average AF burden of 0.6% (range 0% to 3%).
Cardiac imaging
In the population that underwent EP study, the ejection fraction improved from 32.6 ± 3.4% to 56.6 ± 2.0% (p < 0.001) on transthoracic echocardiography, which represented an absolute increase of 24.0 ± 2.5%. RA area decreased from 28.4 ± 2.0 to 20.8 ± 1.2 cm2 (p < 0.001), which represented an absolute decrease of 7.5 ± 1.6 cm2. Similarly, left atrial (LA) area decreased from 32.9 ± 2.3 to 26.8 ± 1.4 cm2 (p = 0.007), which was an absolute improvement of 6.0 ± 1.8 cm2.
On CMR, the ejection fraction improved from 33.6 ± 3.2% to 54.1 ± 3.2% (p = 0.001). Mean LA volume decreased from 107 ± 9.5 to 91.4 ± 3.6 ml (p = 0.08). RA volume decreased from 103.7 ± 14.2 to 78.1 ± 12.5 ml (p = 0.08). Ventricular late gadolinium enhancement was seen in 33.3% of participants at baseline and during follow-up.
EA mapping
RA voltage
Global bipolar voltage increased from 1.58 ± 0.1 to 1.87 ± 0.1 mV (p = 0.04) (Table 2). Tissue voltage increased across all regions, achieving statistical significance at the posterior (absolute increase of 0.52 ± 0.1 mV; p = 0.002) and septal (absolute increase of 0.33 ± 0.1 mV; p = 0.01) segments (Figure 1). The proportion of low voltage decreased by 5.6 ± 2.9%, from 19.7 ± 3.0% to 14.2 ± 3.2% (p = 0.07). The relationship between time from CA versus change in bipolar voltage was determined (Pearson’s correlation coefficient: r = 0.49; p = 0.07).
| Baseline | Follow-Up | Change | p Value | |
|---|---|---|---|---|
| Bipolar voltage | ||||
| Global, mV | 1.58 ± 0.1 | 1.87 ± 0.1 | +0.29 ± 0.1 | 0.04 |
| Anterior, mV | 2.32 ± 0.2 | 2.38 ± 0.2 | +0.06 ± 0.2 | 0.81 |
| Posterior, mV | 1.10 ± 0.1 | 1.62 ± 0.1 | +0.52 ± 0.1 | 0.001 |
| Lateral, mV | 1.63 ± 0.2 | 1.74 ± 0.2 | +0.11 ± 0.2 | 0.60 |
| Septal, mV | 1.22 ± 0.1 | 1.55 ± 0.1 | +0.33 ± 0.1 | 0.01 |
| Low voltage | ||||
| Global, % | 19.7 ± 3.0 | 14.2 ± 3.2 | −5.5 ± 2.9 | 0.07 |
| Anterior, % | 9.4 ± 2.6 | 6.4 ± 2.5 | −3.0 ± 3.5 | 0.41 |
| Posterior, % | 27.4 ± 6.3 | 17.8 ± 5.9 | −9.6 ± 4.3 | 0.04 |
| Lateral, % | 21.7 ± 4.7 | 19.6 ± 3.8 | −2.1 ± 5.5 | 0.71 |
| Septal, % | 19.6 ± 3.8 | 14.6 ± 4.0 | −5.0 ± 4.4 | 0.28 |
| Scar, % | 1.5 ± 1.0 | 0.9 ± 0.5 | −0.6 ± 0.8 | 0.48 |
| Conduction velocity | ||||
| Global, m/s | 0.85 ± 0.0 | 0.89 ± 0.0 | +0.04 ± 0.1 | 0.45 |
| Anterior, m/s | 0.86 ± 0.0 | 0.90 ± 0.1 | +0.04 ± 0.1 | 0.52 |
| Posterior, m/s | 0.78 ± 0.1 | 0.81 ± 0.1 | −0.03 ± 0.1 | 0.73 |
| Lateral, m/s | 0.91 ± 0.1 | 0.87 ± 0.0 | −0.04 ± 0.1 | 0.52 |
| Septal, m/s | 0.86 ± 0.1 | 0.97 ± 0.1 | +0.11 ± 0.1 | 0.08 |
| Fractionation | ||||
| Global, % | 21.7 ± 3.5 | 8.3 ± 1.8 | −13.4 ± 3.6 | 0.002 |
| Anterior, % | 8.9 ± 3.7 | 9.2 ± 4.0 | +0.3 ± 5.3 | 0.97 |
| Posterior, % | 31.1 ± 5.5 | 8.7 ± 1.9 | −22.4 ± 5.5 | 0.001 |
| Lateral, % | 25.2 ± 5.8 | 6.4 ± 1.5 | −18.8 ± 6.2 | 0.009 |
| Septal, % | 24.9 ± 4.6 | 9.3 ± 2.3 | −15.6 ± 4.1 | 0.002 |
Global and Regional RA Bipolar Voltage at Baseline and Follow-Up
Mean bipolar voltage (millivolts) at baseline and follow-up. Overall, there is a significantly higher global voltage at follow-up compared with baseline, with the posterior and septal segments having the highest improvement.
RA conduction
There was no significant difference in global or regional conduction velocity (Figure 2) However, there was a significant reduction in global CFE from 21.7 ± 3.5% at baseline to 8.3 ± 1.8% (p = 0.002) at follow-up. the reduction in CFEs was seen across all regions, including the posterior (31.1 ± 5.5% at baseline to 8.7 ± 1.9%; p = 0.001), lateral (25.2 ± 5.8% to 6.4 ± 1.5%; p = 0.009), and septal (24.9 ± 4.6% to 9.3 ± 2.3%; p = 0.002) walls (Figure 3).
Global and Regional RA Conduction Velocity at Baseline and Follow-Up
Mean conduction velocity (meters per second) at baseline and follow-up. Overall, there were no significant differences in conduction velocity at follow-up compared with baseline.
Global And Regional RA Fractionation at Baseline and Follow-Up
Mean fractionation (%) at baseline and follow-up. Overall, there was a significantly lower fractionation at follow-up compared with baseline, with the posterior, lateral and septal segments having the highest improvement.
Discussion
CA for AF in HF is successful in restoring sinus rhythm and improving ventricular function; however, whether this results in recovery of atrial electrical and structural remodeling has not been reported previously. A subgroup of patients in the CAMERA MRI study who underwent CA with a low incidence of recurrent AF confirmed on continuous monitoring underwent echo, CMR, and RA EA mapping. The main findings were: 1) RA tissue voltage improved significantly, particularly in the posterior and septal regions; 2) the proportion of CFEs was significantly reduced; 3) there were no significant differences in atrial conduction velocities; and 4) there were significant improvements in atrial dimensions and function at a mean follow-up of 23.4 ± 11.9 months.
Recovery of atrial electrical and structural remodeling
Recovery of atrial electrical and structural remodeling has been variably described following the resumption of sinus rhythm. In an animal model of AF, there were persisting ultrastructural changes despite a 4-month restoration of sinus rhythm (14). Teh et al. (15) performed RA mapping in patients >6 months post-CA for paroxysmal AF (15). Despite reduction in LA size and area, the electrical substrate progressed with a decline in mean voltage, with an increase in CFEs with no change in conduction velocity (16). However, in patients with severe mitral stenosis who underwent successful mitral valve commissurotomy, John et al. (17) demonstrated a significant recovery in atrial conduction velocity and tissue voltage that went hand-in-hand with reductions in atrial pressure and dimensions.
The present study in patients with persistent AF and otherwise unexplained systolic HF demonstrated a significant improvement in tissue voltage and reduction in complex atrial electrograms; however, it did not show changes in conduction voltage. However, the changes in voltage that increased in all anatomical regions reached statistical significance in the posterior and septal regions of the RA, with reductions in the proportion of complex atrial electrograms described evenly across all 4 regions. Posterior region of the RA included the crista terminalis, which is a complex anatomical structure with smooth and trabeculated structures that may be more vulnerable to the EA consequences of atrial stretch as well as reverse remodeling when there is some recovery in atrial size.
These differences may partially be explained by differences in the atrial substrate of predominantly reversible cardiomyopathy and reflect the improved outcomes of CA with newer technologies and ablation strategies.
Outcomes of CA for AF in HF: Clinical implications
This study filled existing gaps in the published data concerning atrial remodeling following restoration of sinus rhythm and LV function in AF-mediated cardiomyopathy. The recovery of atrial electrical and mechanical function in the present study might also partially explain the variable response to CA for AF in HF. A meta-analysis of AF ablation in HF suggested that pre-existing structural heart disease, such as previous myocardial infarction, predicted higher AF recurrence (18) and poor recovery of systolic function (19). In a retrospective analysis of 101 patients with persistent AF and HF (LV ejection fraction <45%), patients with no identifiable cause for cardiomyopathy had better outcomes, with a 14% absolute improvement in LV function post-ablation and complete recovery of systolic function in 38% of patients (19). In addition, the maintenance of sinus rhythm post-CA was significantly higher than in patients with known structural heart disease (82% vs. 50%; p = 0.002). The improvements in tissue voltage and reduction in fractionation in the present study might explain this clinical observation.
Study limitations
This was a substudy from a selected group of patients with persistent AF and cardiomyopathy and was not applicable to the general AF population, specifically in those with paroxysmal AF (20). Furthermore, the findings might not apply to patients with structural heart disease, such as valvular heart disease, hypertrophic cardiomyopathy, and pulmonary vascular disease. However, the sample size was small, in keeping with similar mechanistic studies, because only patients willing to return for a follow-up elective EP study could be included. Although it would have been preferable to demonstrate bi-atrial remodeling, the LA was not mapped due to the potential risks associated with nonclinically indicated transseptal puncture and anticoagulation. In addition, previous studies demonstrated that atrial electrical and structural changes in the RA were representative of those seen in the LA (4). In addition, there were similar reductions in size and volume of both the RA and LA, which suggested that the described RA EA changes were likely mirrored in the LA.
Conclusions
Recovery of atrial electrical and structural changes was observed following restoration of sinus rhythm and recovery of LV function in patients who underwent CA for persistent AF and LV systolic dysfunction. This might explain the long-term success of CA in patients with AF and otherwise unexplained cardiomyopathy.
COMPETENCY IN MEDICAL KNOWLEDGE: In patients with AF mediated cardiomyopathy, following restoration of sinus rhythm and recovery of LV function with catheter ablation, there is positive structural and electrical atrial remodeling.
TRANSLATIONAL OUTLOOK: Recovery of atrial structural and electrical changes were demonstrated following restoration of sinus rhythm with CA and recovery of LV systolic function. This may suggest a favorable outcome for patients undergoing CA for AF in the setting of an otherwise unexplained cardiomyopathy.
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Abbreviations and Acronyms
| AF | atrial fibrillation |
| CA | catheter ablation |
| CAMERA-MRI | Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction - Magnetic Resonance Imaging |
| CFE | complex fractionated electrogram |
| CMR | cardiac magnetic resonance |
| EA | electroanatomical |
| Ep | electrophysiology |
| HF | heart failure |
| LA | left atrial |
| LAT | local activation time |
| LV | left ventricular |
| RA | right atrial |
Footnotes
Drs. Sugumar, Prabhu, Voskoboinik and Ling received funding from Australian National Health and Medical Research Council (NHMRC) and/or National Heart Foundation of Australia. Dr. Sugumar has received funding from Royal Australasian College of Physicians and Centre of Research Excellence in Cardiovascular Outcomes Improvement (CRECOI); and has received fellowship support from St Jude Medical and Medtronic. Dr. Prabhu has received fellowship funding from Abbott, Boston Scientific, Biosense Webster, the Heart Foundation, and EHRA. Dr. Ling has received fellowship support from Medtronic, Biotronik and St Jude Medical. Prof. Kalman has received research and fellowship support from St Jude Medical, Medtronic, Biosense Webster, Boston Scientific and Abbott; and has received consultancy fees from Biosense Webster. Prof. Kistler has received consultancy and speaking engagement fees from St Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Andrew Epstein, MD, served as Guest Editor for this paper.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
