Abstract
Background:
Left atrial enlargement and fibrosis have been linked to the pathogenesis of atrial fibrillation (AF). The authors aimed to introduce a novel concept and develop a new procedure for AF treatment based on these characteristics.
Methods:
The study included three stages. The first stage was a descriptive study to clarify the characteristics of the left atrial enlargement and fibrosis’ distribution in patients with mitral valve disease and long-standing persistent AF. Based on these characteristics, the authors introduced a novel concept for AF treatment, and then translated it into a new procedure. The second stage was a proof-of-concept study with this new procedure. The third stage was a comparative effectiveness research to compare the clinical outcomes between patients with this new procedure and those who received Cox-Maze IV treatment.
Results:
Based on the nonuniform fashion of left atrial enlargement and fibrosis’ distribution, the authors introduced a novel concept: reconstructing a left atrium with appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction, and translated it into a new procedure: left atrial geometric volume reduction combined with left appendage base closure. As compared to the Cox-Maze IV procedure, the new procedure spent significantly shorter total surgery time, cardiopulmonary bypass time, and aortic cross-clamp time (P<0.001). Besides, the new procedure was related to a shorter ICU stay period (odd ratio (OR)=0.45, 95% CI=0.26–0.78), lower costs (OR=0.15, 95% CI=0.08–0.29), and a higher rate of A wave of transmitral and transtricuspid flow reappearance (OR=1.76, 95% CI=1.02–3.04).
Conclusions:
The new procedure is safe and effective for eliminating AF associated with mitral valve disease.
Key words: atrial enlargement, atrial fibrillation, fibrosis, mitral valve disease, proof-of-concept, surgery
Background
Highlights
Left atrial spatial enlargement and fibrosis’ regional distribution were not uniform in patients with mitral valve disease and long-standing persistent atrial fibrillation (AF).
This study introduced a new concept for AF elimination: reconstructing a left atrium with an appropriate geometry and uniform fibrosis distribution for conduction, and translated it into a new procedure: left atrial geometric volume reduction combined with left appendage base closure.
This new procedure was a simple and effective approach for AF treatment, which in turn supported that the new concept could be a promising new therapeutic strategy for AF.
Atrial fibrillation (AF) is the most common arrhythmia, with an estimated lifetime risk of 22–26%. AF has been a major health and financial burden globally, which not only results in poor quality of life but also leads to an elevated risk of adverse cardiovascular events and premature mortality1–3. It is reported that AF is present in 30–50% of patients receiving mitral valve surgery, resulting in a higher risk of postoperative death1. Several studies have demonstrated that the addition of surgical ablation in mitral valve surgery was related to a lower rate of AF1. Although several concepts have been applied in the ablation for AF treatment, such as isolating or abolishing the focal sources triggering AF in the pulmonary veins and the ligament of Marshall4,5, the widely accepted concept for AF treatment is still the macro-re-entry circuits blockage by dividing the entire intact atria into many small masses6,7. This concept is the basis of both analogous Cox-Maze procedures and extensive catheter linear ablation7. However, the choice of lesion sets to eliminate AF is widely varied among surgeons during cardiac surgery. Although pulmonary vein isolation is included more commonly than the Cox-Maze procedure due to its simplicity, the effectiveness of pulmonary vein isolation is suggested to be inferior to that of the biatrial maze procedure in most observational studies of patients with long-standing persistent AF8. The complexity of the Cox-Maze procedure precludes it to be broadly implemented, and some other limitations cannot be denied to dividing so many atria for interrupting the macro-re-entry circuits, including prolonged cardiopulmonary bypass and negative impacts on the postoperative left atrial transport functional recovery9,10. Therefore, it is still pivotal to explore the ideal concept for AF elimination during cardiac surgery.
Both left atrial enlargement and fibrosis have been well recognized to play an important role in the pathogenesis of AF, but the underlying mechanisms are unknown, and the characteristics of the left atrial spatial enlargement and fibrosis’ distribution in AF patients remain unclear11–14. We hypothesized that left atrial spatial enlargement and fibrosis’ regional distribution in patients with AF would have their own characteristics and a new concept based on these characteristics would provide a promising strategy for AF treatment. Thus, in the present study, we explored the characteristics of left atrial spatial enlargement and fibrosis’ regional distribution in patients with mitral valve disease and long-standing persistent AF, and based on these characteristics, introduced a new concept, then translated this concept into a new surgical procedure for AF treatment.
Methods
Study design
There were three stages in the study. In the first stage, we explored the left atrial spatial enlargement and fibrosis’ regional distribution in 78 patients with mitral valve disease and long-standing persistent AF. Based on these characteristics, we introduced a new concept for AF treatment: reconstructing a left atrium with an appropriate geometry and uniform fibrosis’ distribution, which we think would regain proper cardiac conduction and consequently treat AF. Then we translated this concept into a new surgical procedure: left atrial geometric volume reduction combined with left appendage base closure. In the second stage, we performed a proof-of-concept study with this procedure in patients with mitral valve disease and long-standing persistent AF with long-standing persistent AF to verify our new concept for AF treatment and assess the efficacy and safety of the new procedure, including a pilot study and a single-arm clinical trial. In the third stage, to further assess the efficacy and safety of the new procedure, we conducted a retrospective comparative effectiveness research, in which we compared the clinical outcomes between patients in the clinical trial group and patients who received Cox-Maze IV treatment. The flowchart is presented in Figure 1. The work has been reported in line with the strengthening the reporting of cohort, cross-sectional and case-control studies in surgery (STROCSS) criteria15, Supplemental Digital Content 1, http://links.lww.com/JS9/A739.
Figure 1.
Flowchart of the study.
Stage I
Participants
We included 78 patients with mitral valve disease and long-standing persistent AF consecutively admitted to our center between January 2015 and December 2016. All patients underwent a combined operation of mitral valve surgery and a Cox-Maze III or IV procedure. Long-standing persistent AF was defined according to the definition in the 2016 ESC guideline, that is, continuous AF for more than 12 months16.
Preoperative left atrial dimensions assessment
Preoperative left atrial dimensions of the patients were measured in three planes of transthoracic two-dimensional echocardiography: anteroposterior, transversal, and superoinferior at end-systole. We calculated the growth rates and the ratio of the three linear diameters to describe left atrial enlargement using the following formula: Growth rate (%) = [(measured value-normal value)/normal value] ×100%. The normal values of Chinese adults have been published before16.
Left atrial tissue fibrosis assessment
Left atrial tissues were collected at seven different locations during the operation, including the appendage, roof, right side wall, left side wall, isthmus, inferior wall, and the center of the pulmonary vein island. Left atrial tissues collected during the operation were then fixed, embedded, cut into slices and stained with Masson trichrome (Trichrome stain kit, TRM-2, ScyTek). Then in each slide, five positions were randomly analyzed by CaseViewer 2.4 (ServiceBio) to calculate the average percentage area (%Area) for interpreting the amount of the collagen fibers in the slide. Tissue fibrosis was quantified using an image processor (Pannoramic Desk, P-MIDI, P250, 3D Histech, Hungary and Caseviewer: C.V 2.3). Fibrosis was calculated using the following formula: Fibrosis (%) = (area of fibrosis/total tissue area) ×100%. Details of assays are described in eMethods, Supplemental Digital Content 2, http://links.lww.com/JS9/A740.
Stage II
Participants
The proof-of-concept study began with a pilot study, encouraged by the results, we further performed a single-arm clinical trial with a larger sample size. In this pilot study, we enrolled 20 patients who were consecutively admitted to our center and satisfied the following inclusions: rheumatic mitral lesions with indication for surgery and without evidence of other concomitant lesions; long-standing persistent AF; tricuspid valve unnecessary for manipulation; 18–60 years old; anteroposterior diameter of left atrial between 45 mm and 60 mm. All eligible patients received concomitant mitral surgery and the new procedure. Next, we further enrolled 120 patients with long-standing persistent AF who had indications of mitral valve surgery regardless of any other concomitant procedures into a single-arm clinical trial. The detailed eligibility criteria and sample size estimation are described in eMethods, Supplemental Digital Content 2, http://links.lww.com/JS9/A740.
A new concept and a new procedure for AF treatment
Based on the results of stage I, we introduced a new concept for AF treatment: reconstructing a left atrium with appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction, and then translated this concept into a new procedure: left atrial geometric volume reduction combined with left appendage base closure.
In order to achieve a left atrium with appropriate geometry, we developed a new geometric volume reduction procedure. Circumferential resection of a strip of the left atrial wall was first performed between the pulmonary veins and the mitral annulus, followed by a longitudinal plication of the pulmonary vein island. Finally, the right side of the island was connected to the interatrial septum instead of the interatrial groove. The circumferential strip resection could effectively decrease the superoinferior diameter, while the pulmonary vein island plication and island attachment on the right side to the intra-atrial septum could mainly reduce the anteroposterior and transversal diameters. After these diameters decreased to the desirable extent, a left atrium with an appropriate geometry could be easily regained.
Since there was a significant difference in fibrosis between both pulmonary vein island/left appendage and the other five sites of the left atrial wall, we could easily create a uniform fibrosis’ distribution for a reduction of conduction dispersion by isolating the pulmonary vein island and closing the left appendage base via ligation or suture in the left atrial wall after excision.
Since pulmonary island isolation was performed by circumferential left atrial strip resection during geometric volume reduction, our new procedure actually contained left atrial geometric volume reduction and left appendage base closure, which can easily reconstruct the left atrium with appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction and consequently treat AF.
Operation
The operation was performed under a median sternotomy and a standard cardiopulmonary bypass with an angled cannula placed in the superior vena cava near its union with the vena anonyme. Multiple antegrade administration of cold blood cardioplegia (4°C) was applied for myocardial protection. The superior vena cava was circumferentially dissected from the right pulmonary artery and pericardium and was transected at least 3 cm cephalad to its entry into the right atrium.
Two circular incisions were performed in the left atrial wall between the pulmonary veins and the mitral annulus. After the first circular incision was made around the pulmonary vein, the left atrium was opened and the pulmonary vein island was totally isolated. The second circular incision was made in the interatrial groove and extended around the mitral annulus, leaving a 2 cm inferior wall margin from the annulus and the appendage in situ. With those two incisions, a circumferential strip of the left atrium was excised. The width of this strip was mainly decided by superoinferior diameter and usually contained less atrial roof and more inferior wall and isthmus. Then the base of the appendage was closed by ligation or excision and suture. After careful mitral manipulations, the pulmonary veins island was longitudinally reef-imbricated with a polypropylene continuous running suture to exclude to the outside of the island. This plicated pulmonary vein island was then anastomosed to the resected margin around the mitral annulus while the right side of the island was directly anastomosed to the longitudinal axis of the atrial septum by the fossa ovarium instead of the interatrial groove. Both the plicated extent of the pulmonary vein island and the anastomotic position in the intra-atrial septum were mainly decided by the anteroposterior and transversal diameters. Finally, superior caval continuity was restored with a running 4-0 polypropylene suture after aortic cross-clamp removal. The main parts of the procedure are presented in Figure 2 and eFigure 1, Supplemental Digital Content 2, http://links.lww.com/JS9/A740. The details of anesthesia procedure and postoperative management are described in eMethods, Supplemental Digital Content 2, http://links.lww.com/JS9/A740.
Figure 2.
Procedure of left atrial geometric volume reduction combined with left appendage base closure. (A) The superior vena cava was transected, and the first left atrial circular incision was performed around the four pulmonary veins. (B) The second circular atrial incision was performed around the mitral annulus. (C) The base of the left appendage was closed by ligation. (D) After mitral manipulations, the pulmonary vein island was longitudinally plicated. (E) The plicated pulmonary vein island was anastomosed to the resected margin around the mitral annulus. (F) The right side of the pulmonary vein island was anastomosed to the intra-atrial septum instead of the interatrial groove.
Outcomes
For efficacy assessment, the primary end point was freedom from AF before discharge, at 3, 6, and 12 months after operation, which was evaluated by 7-day continuous Holter monitoring. No response to treatment was defined as death in the first year; or if patients were too ill to receive assessment; or if patients received any ablation treatment for AF after the index procedure. Secondary end points included the left atrial linear dimensions and A wave reappearance measured by transthoracic echocardiography before discharge, at 3, 6, and 12 months after operation.
For safety assessment, the primary end point included cardiopulmonary bypass time, death, stroke, cardiac resurgery, heart failure, damage to a specialized conduction system which required a permanent pacemaker, renal failure, pneumonia, respiratory failure, infective endocarditis, deep sternal wound infection/mediastinitis, superficial wound infection, sepsis or multiple organ dysfunction syndrome before hospital discharge. Secondary end points included major adverse cardiac events and the incidence of adverse events within 12 months after surgery. Major adverse cardiac events were defined as a nonweighted composite score from: death, worsening heart failure (+1 NYHA Class), hospital admission for heart failure, stroke, and mitral valve reintervention within one year after operation.
Stage III
In order to further assess the efficacy and safety of our new procedure, we performed a comparative effectiveness research to retrospectively compare the clinical outcomes between patients in the clinical trial of the Stage II and patients who received the Cox-Maze IV procedure with radiofrequency. In the corresponding period of the single-arm clinical trial, patients with mitral valve disease and long-standing persistent AF who were consecutively admitted to our center and satisfied the inclusion and exclusion criteria of the clinical trial but refused to be enrolled would be encouraged to undergo the Cox-Maze IV procedure with radiofrequency if their left atrial anteroposterior diameters less than 60 mm. The process of the Cox-Maze IV procedure with radiofrequency has been described in previous literature17. These patients receiving the Cox-Maze IV procedure were included as the control group and a total of 97 patients were finally enrolled. The data of these 97 patients were retrospectively collected, in which freedom from AF was also evaluated by 7-day continuous Holter monitoring. A comparison of the baseline and clinical outcomes between patients in the clinical trial and patients in the ablation group was performed. A number of covariates were assessed between groups, including sex, age, NYHA Class, AF duration, left ventricular ejection fraction, left atrial anteroposterior diameter, mitral lesion, aortic lesion, tricuspid lesion, coronary heart disease, hypertension, prior cerebrovascular accident, diabetes, smoking history, use of amiodarone, use of digoxin, use of beta-blocker, preoperative NT-proBNP level, preoperative creatine level, EuroScore, mitral valve procedure, aortic valve replacement, tricuspid valve repair and coronary artery bypass graft or not. EuroSCORE is the widely-used score to predict the risk of in-hospital mortality after cardiac surgery, calculated by the formula of EuroSCORE I (logistic) including variables of age, sex, chronic pulmonary disease, extracardiac arteriopathy, neurological dysfunction disease, previous cardiac surgery, serum creatinine, active endocarditis, critical preoperative state, unstable angina, LV dysfunction, recent myocardial infarct, pulmonary hypertension, emergency, other than isolated coronary artery bypass graft, surgery on thoracic aorta and postinfarct septal rupture18.
Statistical analysis
The mean ± SD was used to describe continuous variables and percentages was used for categorical variables. We tested the normal distribution and homogeneity of variance for all indicators. A one-way analysis of variance (ANOVA) was used to compare the growth rate between diameters, and the fibrosis between different sites. Post-hoc tests were performed by using the least significant difference test. A repeated measures ANOVA was conducted to investigate the changes in each linear diameter before and after operation. χ 2-test was used to examine the difference for categorical variables and the Student t-test for continuous variables in comparative effectiveness research. Logistic regression was used to assess the association of new procedure with the outcomes as compared to the Cox-Maze IV procedure, in which covariables with significant difference between groups were included in multivariable models.
All analyses were performed by using SPSS 22.0 version and SAS 9.4, and P<0.05 was considered as statistically significant.
Result
Stage I
The baseline characteristics of 78 patients are presented in Table 1. The anteroposterior, transversal, and superoinferior diameters of the left atrium increased but with significantly different growth rates (Table 1, P<0.05). A disproportionate increase was observed between these three diameters. The ratio between anteroposterior, transversal, and superoinferior diameter was 1.00:1.04:1.28 in AF patients, which was different from the normal ratio (1.00:1.08:1.40). As a result, the shape of left atrium changed from ellipse to near-spheroid. Fibrosis among the seven sites of the left atrium was significantly different (P<0.05). Fibrosis was most severe in the center of the pulmonary vein island and least severe in the appendage, while the severity of fibrosis at the other five sites was similar (Fig. 3, Table 1 and eTable 1, Supplemental Digital Content 2, http://links.lww.com/JS9/A740). Besides, we performed cardiac magnetic resonance imaging to assess the fibrosis’ distribution for two cases who agreed to receive the examination, which showed similar distributions (Fig. 4).
Table 1.
Characteristics, left atrial geometry, and fibrosis assessment among 78 patients with long-standing persistent AF at Stage I.
| Characteristic | Value |
|---|---|
| Sex, no. (male/female) | 78 (36/42) |
| Age, years | 55.9±9.9 |
| BMI-kg/m2 | 22.6±3.6 |
| NYHA Class | |
| II, no. (%) | 4 (5.1) |
| III, no. (%) | 62 (79.5) |
| IV, no. (%) | 12 (15.4) |
| Mitral stenosis, no. (%) | 5 (6.4) |
| Mitral regurgitation, no. (%) | 12 (15.4) |
| Mitral stenosis+regurgitation, no. (%) | 26 (33.3) |
| Double or triple valve lesions, no. (%) | 35 (44.9) |
| Mitral etiology | |
| Rheumatic, no. (%) | 66 (84.6) |
| Degenerative, no. (%) | 12 (15.4) |
| Comorbidity | |
| Hypertension, no. (%) | 7 (9.0) |
| Diabetes, no. (%) | 5 (6.4) |
| Chronic renal failure, no. (%) | 3 (3.8) |
| Prior cerebrovascular accident, no. (%) | 8 (10.3) |
| Mitral surgery | |
| Repair, no. (%) | 10 (12.8) |
| Replacement, no. (%) | 68 (87.2) |
| Concomitant procedures | |
| Aortic valve replacement, no. (%) | 22 (28.2) |
| Tricuspid repair, no. (%) | 27 (34.6) |
| Left atrial geometry assessment | |
| Diameter | |
| Anteroposterior (AP) | 54.7±11.2 |
| Transversal (T) | 56.7±12.4 |
| Superoinferior (SI) | 70.1±11.7 |
| Growth rate (%)* | |
| Anteroposterior (AP) | 86.5±38.2 |
| Transversal (T) | 85.5±38.5 |
| Superoinferior (SI) | 70.1±28.4 |
| Fibrosis assessment | |
| Appendage (%) | 28.0±9.3 |
| Roof (%) | 38.2±14.0 |
| Left side wall (%) | 35.4±15.8 |
| Right side wall (%) | 38.8±10.9 |
| Inferior wall (%) | 37.9±15.8 |
| Isthmus (%) | 37.8±11.3 |
| Central pulmonary veins island (%) | 51.3±13.7 |
P value for growth rate: p (AP versus T)=0.860; p (AP versus SI)=0.004; p (T versus SI)=0.007.
Figure 3.
Fibrosis assessment at seven left atrial sites among patients with mitral valve disease and long-standing persistent AF. (A) Stage I; (B) Stage II: the pilot study; (C) Stage II: the clinical trial.
Figure 4.
Cardiac magnetic resonance imaging of fibrosis distribution of two cases with valvular disease and long-standing persistent atrial fibrillation. (A) First case: Back view; (B) First case: Front view; (C) First case: Top view; (D) First case: Lateral view; (E) Second case: Back view; (F) Second case: Front view; (G) Second case: Top view; (H) Second case: Lateral view.
Based on these results, we introduced a concept for AF treatment: reconstructing a left atrium with appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction; and then translated this concept into a new procedure: left atrial geometric volume reduction combined with left appendage base closure.
Stage II: Pilot study
All 20 patients successfully underwent the new surgical procedure for AF treatment and concomitant mitral valvular replacement with a mechanical prosthesis. The cardiopulmonary bypass time and aortic cross-clamping time were 95.5±19.0 min and 44.4±17.8 min, respectively (Table 2). The satisfied left atrial appendage closure was confirmed by intraoperative transesophageal echocardiography in all cases. During the operation, we also collected the tissues to measure the fibrosis among the seven sites for these patients. As shown in Figure 3, fibrosis of the left atrium was significantly different (P<0.05), indicating that left atrial fibrosis’ distribution was uneven. The most severe fibrosis was in the center of the pulmonary vein island and the least severe in the appendage, while fibrosis was similar among the other five sites. After the operation, left atrial anteroposterior, transversal, and superoinferior diameters decreased significantly (P<0.05, Fig. 5 and eTable 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A740). The reduction of anteroposterior and transversal diameters was more prominent than that of superoinferior diameter (P<0.05, Fig. 5 and eTable 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A740). The ratio of diameter in the left atrium (anteroposterior: transversal: superoinferior) was 1.00:1.09:1.36 (Fig. 5 and eTable 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A740). It showed that the left atrial shape returned to the normal elliptical shape. The three diameters kept stable within the 3-year follow-up. Figure 6 presents the change of left atrial geometry before and after a new procedure for one patient.
Table 2.
Baseline and operative characteristics of patients at Stage II and III.
| Characteristic | Pilot study (N=20) | Clinical trial (N=120) | Ablation (N=97) | P * |
|---|---|---|---|---|
| Sex, no (male/female) | 20 (7/13) | 120 (46/74) | 97 (38/59) | 0.899 |
| Age, years | 49.6±9.6 | 52.3±8.0 | 56.7±8.7 | <0.001 |
| NYHA Class III or Class IV, no. (%) | 20 (100) | 112 (93.3) | 84 (86.6) | 0.095 |
| Atrial fibrillation duration, months | 19.4±6.5 | 23.6±9.7 | 21.5±8.1 | <0.001 |
| Left ventricular ejection fraction, n (%) | 57.1±8.1 | 60.5±8.7 | 61.0±9.3 | 0.708 |
| Left atrial anteroposterior diameter, mm | 55.0±3.3 | 54.8±9.3 | 51.5±8.3 | 0.007 |
| Mitral lesion, no. (%) | 20 (100) | 120 (100) | 89 (91.8) | 0.004 |
| Aortic lesion, no. (%) | 0 | 58 (48.3) | 52 (53.6) | 0.44 |
| Tricuspid lesion, no. (%) | 0 | 85 (70.8) | 79 (81.4) | 0.071 |
| Coronary Heart Disease, no. (%) | 0 | 3 (2.5) | 1 (1.0) | 0.77 |
| Hypertension, no. (%) | 1 (5.0) | 13 (10.8) | 7 (7.2) | 0.36 |
| Prior cerebrovascular accident, no. (%) | 0 | 12 (10) | 9 (9.3) | 0.858 |
| Diabetes, no. (%) | 1 (5.0) | 5 (4.2) | 6 (6.2) | 0.717 |
| Smoking history, no. (%) | 2 (10.0) | 25 (20.8) | 11 (11.3) | 0.062 |
| Use of amiodarone, no. (%) | 1 (5.0) | 3 (2.5) | 5 (5.2) | 0.484 |
| Use of digoxin, no. (%) | 11 (55.0) | 69 (57.5) | 47 (48.5) | 0.241 |
| Use of beta-blocker, no. (%) | 5 (25.0) | 23 (19.2) | 49 (50.5) | <0.001 |
| Preoperative NT-proBNP level, pg/ml | 1553.2±1233.2 | 1482.3±1321.8 | 1486.7±1470.9 | 0.982 |
| Preoperative creatine level, μmol/l | 77.5±16.3 | 79.4±44.9 | 78.1±18.4 | 0.219 |
| EuroScore I | 1.8±1.6 | 1.8±1.4 | 1.8±1.5 | 0.842 |
| Mitral valve procedure, no. (%) | ||||
| Mitral valve replacement | 20 (100) | 109 (90.8) | 88 (90.7) | 0.977 |
| Mitral valve repair | 0 | 11 (9.2) | 9 (9.3) | 0.807 |
| Aortic valve replacement, no. (%) | 0 | 35 (29.2) | 20 (20.6) | 0.15 |
| Tricuspid valve repair, no. (%) | 0 | 38 (31.7) | 33 (34.0) | 0.713 |
| CABG, no. (%) | 0 | 3 (2.5) | 0 | 0.325 |
| Blood loss, ml | 216.5±127.0 | 260.8±158.7 | 317.7±176.5 | 0.013 |
| Extubation time, h | 14.3±8.28 | 13.6±10.8 | 20.6±20.9 | 0.003 |
| Total surgery time, min | 221.6±33.9 | 230.7±48.4 | 284.4±47.4 | <0.001 |
| Total cardiopulmonary bypass time, min | 95.5±19.0 | 106.8±33.4 | 169.3±39.1 | <0.001 |
| Aortic cross-clamp time, min | 44.4±17.8 | 52.5±23.5 | 108.2±24.6 | <0.001 |
P value was obtained by the comparison between clinical trial group and ablation group.
Figure 5.
Changes of left atrial anteroposterior (LA-AP), transversal (LA-T), and superoinferior diameters (LA-SI) at Stage II. (A) The pilot study; (B) The clinical trial.
Figure 6.
Computed tomography imaging for the left atrial geometry before and after new procedure of one case with mitral valve disease and long-standing persistent atrial fibrillation. (A) Before procedure; (B) After procedure.
The sinus rhythm was restored in all patients after the procedure. During the 1-year follow-up, sinus rhythm was preserved in all patients. No atrioventricular conduction disturbances were reported (Table 3). Before discharge, the A wave of transmitral and transtricuspid flow reappeared among 17 patients (85%) before discharge, thereafter reappeared among 17 (85%), 18 (90%), and 18 (90%) at 3, 6, and 12 months, respectively (Table 3). There was no uncontrollable bleeding caused by left atrial anastomoses. No additional surgery was performed for postoperative bleeding. One patient (5%) had pneumonia (Table 3). No renal failure cerebrovascular events, or other adverse events occurred (Table 3).
Table 3.
Clinical end points and adverse events among patients at stage II and III.
| End point or event | Pilot study (N=20) | Clinical trial (N=120) | Ablation (N=97) | P * |
|---|---|---|---|---|
| Clinical end points before discharge, N (%) | ||||
| Sinus rhythm restoration | 20 (100) | 96 (80.0) | 69 (71.1) | 0.128 |
| A wave of transmitral and transtricuspid flow reappearance | 17 (85) | 76 (63.3) | 48 (49.5) | 0.01 |
| Hours of ICU stay | 24.5 (21.0, 44.5) | 29.0 (23.3, 49.0) | 40.0 (26.0, 65.5) | 0.006 |
| Total hospitalized cost (USD) | 12899.3 (11 594, 13 762) | 16863.8 (14 524.1, 20 790.1) | 22 551.4 (18708.1, 26 429.9) | <0.001 |
| Death | 0 | 2 (1.67) | 1 (1.03) | 0.999 |
| Clinical end points at 12 months after operation, N (%) | ||||
| Sinus rhythm restoration | 20 (100) | 98 (81.7) | 71 (73.2) | 0.135 |
| A wave of transmitral and transtricuspid flow reappearance | 18 (90) | 84 (70) | 58 (59.8) | 0.116 |
| Death | 0 | 4 (3.33) | 2 (2.06) | 0.627 |
| Stroke | 0 | 2 (1.67) | 1 (1.03) | 0.999 |
| Reoperation | 0 | 1 (0.83) | 1 (1.03) | 0.999 |
| Heart failure | 0 | 1 (0.83) | 1 (1.03) | 0.999 |
| Permanent pacemaker implantation | 0 | 1 (0.83) | 3 (3.09) | 0.47 |
| Composite end point | 0 | 8 (6.7) | 7 (7.2) | 0.874 |
| Renal failure | 0 | 4 (3.33) | 4 (4.12) | 0.999 |
| Pneumonia | 1 (5) | 6 (5) | 6 (6.19) | 0.704 |
| Respiratory failure | 0 | 2 (1.67) | 1 (1.03) | 0.999 |
| Infective endocarditis | 0 | 1 (0.83) | 0 | 0.999 |
| Deep sternal infection | 0 | 1 (0.83) | 1 (1.03) | 0.999 |
| Superficial wound infection | 0 | 2 (1.67) | 1 (1.03) | 0.999 |
| Sepsis | 0 | 1 (0.83) | 0 | 0.999 |
| Multiple organ dysfunction syndrome | 0 | 1 (0.83) | 1 (1.03) | 0.999 |
P value was obtained by the comparison between clinical trial group and ablation group.
The end of this study was in March 2021. The mean duration of follow-up was 39.7±2.9 months. No late deaths or major adverse cerebrovascular events were observed. All patients returned to normal life with NYHA functional class I or II.
Stage II: Clinical trial
A total of 120 patients were enrolled during the period of August 2018 and March 2020. The baseline and operative information of patients are presented in Table 2. The aortic cross-clamp time and the cardiopulmonary bypass time were 52.5±23.5 min and 106.8±33.4 minutes, respectively (Table 2). Intraoperative transesophageal echocardiography showed that the left atrial appendage was perfectly closed in all patients. Analysis for fibrosis showed a significant difference among seven sites of the left atrium was observed (P<0.05), indicating that left atrial fibrosis’ distribution was not uniform. Fibrosis was most severe in the center of the pulmonary vein island and least severe in the appendage, while fibrosis was similar among the other 5 sites (Fig. 3). After operation, all the anteroposterior, transversal, and superoinferior diameters of the left atrium decreased (P<0.05, Fig. 5 and eTable 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A740). The reduction of anteroposterior and transversal diameters were greater than that of superoinferior diameter (P<0.05). The ratio of diameter (anteroposterior: transversal: superoinferior) was 1.00:1.07:1.39 after surgery, which was 1.00:1.09:1.32 before surgery (Fig. 5 and eTable 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A740), indicating the left atrium returned to the normal elliptical shape after surgery. The diameters remained stable for at least 12 months.
A total of 96 patients restored sinus rhythm before discharge, accounting for 80%. The number (percentage) was 97 (80.8%), 98 (81.7%), or 98 (81.7%) at 3, 6, 12 months after the procedure, respectively (Table 3). The number of patients with left atrial A wave was 76 (63.3%) among the patients with sinus rhythm restoration after operation and increased to 84 (70%) during 1-year after operation (Table 3).
As shown in Table 3, two patients died (1.67%) before discharge due to postoperative multiorgan failure and sepsis, respectively. During 1-year after procedure, four patients (3.33%) died, two (1.67%) developed stroke, one (0.83%) received resurgery, and the rate of adverse events was relatively low, including pneumonia (5.0%), acute renal failure (3.33%), etc. (Table 3).
Stage III
In Table 2, although patients in clinical trial group were older than the comparison group, patients in clinical trial group were at a poorer health status than patients in Cox-Maze IV treatment group at baseline, including a longer duration of AF, a larger left atrium, and more patients with mitral lesion. Total surgery time, cardiopulmonary bypass time, aortic cross-clamp time, and extubation time consumed in the clinical trial were significantly shorter than that in Cox-Maze IV group (total surgery time (min): 230.7±48.4 versus 284.4±47.4; cardiopulmonary bypass time (min): 106.8±33.4 versus 169.3±39.1; aortic cross-clamp time (min): 52.5±23.5 versus 108.2±24.6; P<0.001; extubation time (h): 13.6±10.8 versus 20.6±20.9; P=0.003), the amount of blood loss in the clinical trial were significantly less than that in the Cox-Maze IV group (260.8±158.7 ml vs. 317.7±176.5 ml; P=0.013). In Tables 3 and 4, new procedure was related to a shorter ICU stay period (crude odd ratio (OR)=0.45, 95% CI=0.26–0.78), lower costs (crude OR=0.15, 95% CI=0.08–0.29), and a higher rate of A wave of transmitral and transtricuspid flow reappearance (crude OR=1.76, 95% CI=1.02–3.04) before discharge although the association kept significance only with lower costs in the multivariable model (adjusted OR=0.18, 95% CI=0.08–0.39). No significant differences were found between the two groups regarding the rate of sinus rhythm restoration, left atrial A wave reappearance and other clinical outcomes within one year after procedure.
Table 4.
Odds ratio of clinical end points and adverse events by comparing clinical trial group to ablation group at Stage III.
| Crude | Adjusted* | |||
|---|---|---|---|---|
| End point or event | OR (95% CI) | P | OR (95% CI) | P |
| Clinical end points before discharge, N (%) | ||||
| Sinus rhythm restoration | 1.62 (0.87–3.04) | 0.13 | 1.55 (0.75–3.22) | 0.241 |
| A wave of transmitral and transtricuspid flow reappearance | 1.76 (1.02–3.04) | 0.041 | 1.49 (0.79–2.82) | 0.223 |
| ICU stay period (h) | 0.45 (0.26–0.78) | 0.046 | 0.70 (0.36–1.34) | 0.283 |
| Total hospitalized cost (USD) | 0.15 (0.08–0.29) | <0.001 | 0.18 (0.08–0.39) | <0.001 |
| Death | 1.63 (0.15–18.22) | 0.693 | 1.85 (0.11–30.79) | 0.667 |
| Clinical end points at 12 months after operation, N (%) | ||||
| Sinus rhythm restoration | 1.63 (0.86–3.11) | 0.137 | 1.91 (0.90–4.05) | 0.09 |
| A wave of transmitral and transtricuspid flow reappearance | 1.57 (0.89–2.76) | 0.117 | 1.32 (0.68–2.57) | 0.406 |
| Death | 1.64 (0.29–9.14) | 0.573 | 1.48 (0.21–10.57) | 0.694 |
| Stroke | 1.63 (0.15–18.22) | 0.693 | 1.20 (0.08–17.92) | 0.897 |
| Reoperation | 0.81 (0.05–13.07) | 0.88 | 0.86 (0.03–24.87) | 0.932 |
| Heart failure | 0.81 (0.05–13.07) | 0.88 | – | |
| Permanent pacemaker implantation | 0.26 (0.03–2.57) | 0.251 | 0.97 (0.05–17.86) | 0.981 |
| Composite end point | 0.92 (0.32, 2.63) | 0.874 | 1.22 (0.35–4.33) | 0.754 |
| Renal failure | 0.80 (0.20–3.29) | 0.759 | 0.73 (0.15–3.53) | 0.691 |
| Pneumonia | 0.80 (0.25–2.56) | 0.705 | 0.59 (0.15–2.33) | 0.455 |
| Respiratory failure | 1.63 (0.15–18.22) | 0.693 | 1.43 (0.07–28.44) | 0.817 |
| Infective endocarditis | – | – | ||
| Deep sternal infection | 0.81 (0.05–13.07) | 0.88 | 1.03 (0.03–37.07) | 0.988 |
| Superficial wound infection | 1.63 (0.15–18.22) | 0.693 | 1.43 (0.07–28.02) | 0.814 |
| Sepsis | – | – | ||
| Multiple organ dysfunction syndrome | 0.81 (0.05–13.07) | 0.88 | 0.03 (0.001–3.87) | 0.155 |
Adjusted for age, atrial fibrillation duration, left atrial anteroposterior diameter, mitral lesion, and use of beta-blocker at baseline.
Discussion
In the current study, we found that left atrial spatial enlargement and fibrosis’ distribution were not uniform in patients with mitral valve disease and long-standing persistent AF. Based on this finding, we introduced a new concept for treating AF: reconstructing a left atrium with an appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction. Then, we translated this concept into a new procedure: left atrial geometric volume reduction combined with left appendage base closure. Results from the pilot study, the single-arm clinical trial, and the comparative effectiveness research, demonstrated that this new procedure was a simple and effective approach for AF treatment, which in turn supported that our concept could be the promising new therapeutic strategy for AF.
Both left atrial enlargement and fibrosis play an important role in the pathogenesis of AF, but the underlying mechanisms are unclear13. Because the left atrium is a geometric cavity, its enlargement might involve not only the size but also the shape. AF was always accompanied by a left atrium with large size and a left atrium with large size indicated a poor prognosis after surgical or catheter treatment. A few recent studies showed that the left atrial shape change was also associated with AF pathogenesis and it would change from a normal ellipse to a near-spheroid in AF patients17,19. However, the characteristics of the left atrial spatial enlargement have not been clearly elucidated. In the present study, we found that the left atrial spatial enlargement was in a uniform fashion: the growth rates of the anteroposterior and transversal diameters were significantly higher than that of the superoinferior diameter. As a result, the left atrium changed from a normal elliptical shape to a near-spherical shape. The size of the left atrium determines the cardiac conduct distance within the atrium. The left atrial enlargement is uneven in both size and shape, resulting in the disproportionate distance increase in different directions inside the enlarged left atrium, which might induce AF20,21. Left atrial fibrosis is also a risk factor for AF pathogenesis. Previous studies have shown that increased atrial fibrosis was associated with more frequent paroxysms of AF, the transformation of AF into a persistent type, and reduced effectiveness of medical, catheter, or Cox-Maze procedure therapy22–26. However, in most of those studies, left atrial samples for fibrosis assessment were collected from a single site during the open heart surgery, which did not represent the overall condition of atrial fibrosis. Recently, several AF studies provided evidence from post-mortem autopsy findings, delayed enhancement-MRI investigations in patients and myocardial histologic analyses in an animal model indicated that left atrial fibrosis’ regional distribution was in a nonuniform fashion24,27,28. Our present study confirmed this uneven fibrosis’ regional distribution in AF patients and further summarized the characteristics: fibrosis in the pulmonary vein island or in appendage was significantly different from other sites of the left atrial wall. The atrial tissue is the media for cardiac conduction, so uneven fibrosis serves as a heterogeneous media for conduction, which might cause abnormal conduction and AF22–26. So it is plausible that a reduction of conduction dispersion can be achieved by removing the areas with heterogeneous fibrosis at key sites of the left atrium. Therefore, we hypothesized that reconstructing a left atrium with appropriate geometry and uniform fibrosis’ distribution could achieve normal cardiac conduction and consequently restore sinus rhythm.
Reconstructing a left atrium with an appropriate geometry with uniform fibrosis’ distribution could be easily achieved by our newly-developed procedure: left atrial geometric volume reduction combined with left appendage base closure. In our left atrial geometric volume reduction, resection of the circumferential left atrial strip can decrease the superoinferior diameter, while pulmonary vein island plication and connection of the right side of the island to the interatrial septum can reduce both anteroposterior and transversal diameters. When those three left atrial diameters were decreased to a desirable extent, a left atrium with a normal elliptical shape and an appropriate size was successfully reconstructed, which was confirmed by echocardiography in our present study. Our study found that fibrosis in both the pulmonary vein island and left appendage were significantly different from that in other left atrial sites, so a left atrial uniform fibrosis’ distribution could be produced by the pulmonary vein island isolation and the appendage base closure. In our procedure, the pulmonary vein island isolation was completed by the left atrial geometric volume reduction. Therefore, left atrial geometric volume reduction combined with left appendage base closure could effectively reconstruct a left atrium with appropriate geometry and uniform fibrosis’ distribution for proper cardiac conduction.
Although several surgical techniques on the basis of different concepts have been applied to treat AF, the cut-and-sew Cox-Maze III is still the mainstream surgery for AF treatment, which is based on the concept to divide the atrial wall into many small areas which are electrically isolated from each other and not large enough to sustain the macro-re-entry circuits6,7. However, several obvious limitations inhibit its widespread adoption, including the time-consuming process, complex and risk incisions in both atria29. A more practical procedure, known as Cox-Maze IV, has been developed and widely accepted as the preferred technique for AF elimination, in which the classic cut-and-sew lesions are replaced with ablative lines using various energy sources29. Therefore, in order to further assess the efficacy and safety of our new procedure, we retrospectively compared the results of our clinical trial with that of the widespread-applied Cox-Maze IV treatment in the third stage of this study. As compared to patients with Cox-Maze IV treatment, patients with our new procedure had similar incidence of postoperative sinus rhythm, experienced a shorter cardiopulmonary bypass time, had a significantly higher rate of A wave reappearance and lower costs, although they were at a poorer condition and had a larger left atrium. These results demonstrated that our new procedure was a simple and effective approach for AF treatment and might be a better choice for those patients with an enlarged left atrium. Three major reasons might contribute to this acceptable consequence. First, our procedure could provide excellent exposure of surgical field and comfortable access to all parts of the left atrium and mitral valve by routine superior vena caval transection. Secondly, much less manipulations in the left atrial wall were necessary in our procedure than in the Cox-Maze IV procedure, which would improve the left atrial transport functional recovery after appearance of sinus rhythm. In patients with reappearance of sinus rhythm after Cox-Maze procedures, the left atrial transport functional recovery rates were reported in literature about 60%9. However, it was about 70% in our study. Thirdly, a left atrium with appropriate geometry could easily be obtained by our procedure, which might benefit the maintenance of sinus rhythm after AF treatment. During Cox-Maze procedures, concomitant left atrial partial wall resection could significantly improve sinus rhythm restoration as compared to the Cox-Maze procedure alone30. However, this concomitant left atrial volume reduction was rarely performed due to extra aortic cross-clamp time in clinical practice. Furthermore, most procedures for left atrial partial volume reduction paid little attention to left atrial shape31,32. Emerging evidence suggested that both left atrial size and shape are important factors of AF recurrence17,19, so our procedure might contribute to the maintenance of sinus rhythm.
Our new concept could provide a new insight into AF pathogenesis and treatment. Because our present study was conducted in patients with mitral valve disease and long-standing persistent AF, we believe that the new concept and the procedure will be suitable for AF associated with mitral valve disease, while if this new concept and the procedure could be generalized to treat patients with only AF should be further assessed. However, it is expected to be suitable for lone AF treatment because patients with lone AF have the same left atrial structural remodeling (enlargement and fibrosis)12,13. Recently, we performed our new procedure in five cases with alone AF who had complication of left atrial rupture or left atrial esophageal fistula during or after transcatheter radiofrequency ablation and still remained in AF state. All these five patients survived and continuously remained in sinus rhythm after our surgery and during the 5 to 37 months follow-up. The details of the one case with left atrial esophageal fistula has been described in our recent report33. These limited data supported that our new concept and procedure might be suitable for the treatment of alone AF.
Although our new procedure is a cut-and-sew procedure, it is not a modified procedure of previous procedures (e.g. Cox-Maze III) but a procedure based on a brand-new concept for AF treatment. Furthermore, we believe that it would probably be completed by minimally invasive surgery. The volume reduction and shape reconstruction could be achieved as the left ventricular aneurysm linear plication with the Bioventrix Revivent Anchoring system34, pulmonary vein island isolation could be finished with ablation and the left appendage base would be closed with clips.
There were several limitations of the present study. First, the single-arm design of the proof-of-concept study cannot allow us to compare the efficacy of the new procedure with the gold standard treatment, while we performed a comparative effectiveness research, which indicated a better efficacy of the new procedure than the standard treatment. Second, although a number of covariates have been adjusted in multivariable model to reduce potential bias, bias from unmeasured confounders might play a role in the results. Third, the follow-up is not long enough to assess the long-term outcomes. Thus, a randomized controlled trial with longer follow-up is needed to confirm the efficacy and safety of the novel procedure. Fourth, the method used to assess fibrosis’ distribution in this study is limited to provide a high-resolution global fibrosis’ distribution. Cardiac MRI is needed to assess if the uniform global fibrosis’ distribution could be achieved after the procedure in the future randomized controlled trial. Fifth, this study was conducted among patients from a single hospital, the results should be interpreted with caution regarding the generalizability.
In conclusion, our present study introduced a new concept and translated it into a new procedure. The new procedure is safe and effective for eliminating AF associated with mitral valve disease. We believe it would provide a new insight into AF pathogenesis and treatment.
Ethical approval
The ethics committee of Union Hospital Fujian Medical University approved this study. (No. FJXH2016003).
Consent
Written informed consent was obtained from the patient's parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editorin-Chief of this journal on request.
Sources of funding
This work was supported by the Major Science and Technology Project of Fujian Provincial Health Commission (2022ZD01004) to Dr Liangwan Chen. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Author contribution
All authors contributed to the study design, interpretation of data, and revise it for important intellectual content. L.W.C.: led development and implementation of the exercise interventions; L.W.C., Q.Z.L., Y.S., G.H.F., and H.L.: trained physiotherapists and monitored intervention fidelity; J.Y.C. and M.R.T. conducted the statistical analysis: Q.S.W.: provided statistical and trial design expertise; Q.Z.L. provided trial management expertise; L.W.C., Q.Z.L., Y.S., G.H.F., and H.L.: provided clinical expertise; L.W.C., J.Y.C., and L.M.L.: led on writing the manuscript. All authors read, commented on, and approved the final version. Z.H.Q., M.R.T., and X.F.D.: verified the underlying data. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Conflicts of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
ClinicalTrials.gov: NCT 03347695. https://clinicaltrials.gov/ct2/show/NCT03347695?term=NCT+03347695&draw=2&rank=1.
Guarantor
Liangwan Chen.
Data availability statement
Individual participant data will be made available on request to the corresponding author.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Supplementary Material
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.
Published online 21 June 2023
Contributor Information
Liangwan Chen, Email: chenliangwan@fjmu.edu.cn.
Qianzhen Li, Email: doctorlqz@163.com.
Junyi Chen, Email: FireFeuer@126.com.
Zhihuang Qiu, Email: qzhflm@126.com.
Jun Xiao, Email: xiaojun@fjmu.edu.cn.
Mirong Tang, Email: 449054039@qq.com.
Qingsong Wu, Email: wqs9005@163.com.
Yue Shen, Email: 181633292@qq.com.
Xiaofu Dai, Email: 1470054258@qq.com.
Guanhua Fang, Email: fangguanhua2502@163.com.
Heng Lu, Email: luheng1997@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Individual participant data will be made available on request to the corresponding author.