Abstract
Objective: Atrial dilatation and fibrosis are considered to be important factors in the occurrence and maintenance of atrial fibrillation (AF). However, the relationship between those structural remodeling and postoperative sinus conversions after a maze operation has been rarely studied. The purpose of this study was to determine whether pathological evaluation of atrial tissues was useful for predicting an unsuccessful maze operation in patients with valvular AF. Methods: Between March 2006 and June 2007, left-atrial tissues in the posterior wall and right-atrial appendage were obtained from 47 consecutive patients (24 patients with chronic AF, and 23 with sinus rhythm) undergoing mitral valve surgery (MVS). A concomitant maze operation was performed for all patients with chronic AF. Atrial cell diameters were measured using hematoxylin and eosin staining, and quantitative assessment of atrial fibrosis was performed with Masson trichrome staining using an image analyzer (Image Processor for Analytical Pathology, Sumika Technoservice Co., Hyogo, Japan). Results: Successful MVS was performed for all patients and there were no complications associated with tissue sampling. Patients with chronic AF had more advanced histological features in both atria as compared with those with sinus rhythm. Sixteen of 24 patients, who underwent a maze operation, had successfully restored sinus rhythm (successful maze group), while that in the remaining eight was not restored (unsuccessful maze group). Patients in the unsuccessful maze group had a larger left-atrial dimension and cardiothoracic ratio as compared with those in the successful group, whereas the duration of AF was not significantly different. Patients in the unsuccessful maze group also had greater hypertrophy of cardiomyocytes and more extensive intercellular fibrosis in the left atrium, while there were no differences for right-atrial pathological features between the groups. Multivariate logistic analysis confirmed that a larger amount of left-atrial fibrosis (>15%) was significantly associated with an unsuccessful maze operation. Conclusions: The present results suggested that advanced fibrosis in the left atrium, but not in the right atrium, might be significantly associated with an unsuccessful maze operation in patients with valvular AF.
1 Introduction
Atrial fibrillation (AF) is the most significant type of arrhythmia in patients with mitral valve disease (MVD), which impairs cardiac function and is associated with an increased risk of systemic embolization and mortality [1, 2]. First-line therapy for AF is pharmacological treatment, while a maze operation is performed for AF that is refractory to medical treatment. The maze procedure, initially described by Cox and colleagues, has been proven to be safe and extremely effective for surgical treatment of AF, and is most often used in patients undergoing mitral valve surgery (MVS) to enhance the probability of postoperative restoration of sinus rhythm [3, 4]. Although several studies have indicated that clinical factors including advanced age, larger left-atrial diameter, lower amplitude of the f-wave in the V1 lead, and longer duration of AF are independent predictors associated with postoperative recurrence of AF after a maze procedure [5–7], this issue still remains controversial.
These risk factors also cause structural atrial changes, including dilatation and fibrosis, which are believed to be major arrhythmogenic factors [8]. Moreover, AF, by itself, induces electrical and structural changes in the atrium favoring its persistence [9]. Although histological changes of atrial tissues have been studied in patients with AF [8, 10, 11], its pathophysiology is incompletely understood. Furthermore, few studies have investigated the associations between atrial histological changes and successful sinus conversion after a maze operation [12]. The purpose of this study was to investigate cellular changes in patients with valvular AF and determine whether histological evaluation of atrial tissues might be useful for predicting an unsuccessful maze operation for valvular AF.
2 Materials and methods
Between March 2006 and June 2007, left-atrial tissues in the posterior wall and right-atrial appendage were obtained from 47 consecutive patients (24 patients with chronic AF and 23 with sinus rhythm) undergoing MVS. A concomitant maze operation was performed for all patients with chronic AF. Preoperative atrial rhythm was established by 24-h electrocardiogram Holter monitoring performed in the preceding months. Patients with paroxysmal AF, history of cardiac surgery, endocarditis, or acute mitral valve regurgitation were excluded from this study. Twenty-four patients with preoperative chronic AF were classified into two groups: those who had successfully restored sinus rhythm postoperatively and maintained after 3 months (n =16, successful maze group), and those without restored sinus rhythm despite the use of antiarrhythmic drugs or electrical cardioversion (n =8, unsuccessful maze group).
This study was approved by the Institutional Human Research Committee of Sakurabashi Watanabe Hospital and adhered to the principles outlined in the Declaration of Helsinki. All patients gave written informed consent for participating in the study. The baseline characteristics in patients with preoperative AF are presented in Table 1 .
Patient characteristics in patients with valvular AF.
2.1 Echocardiography
Two-dimensional and Doppler transthoracic echocardiography (TTE) examinations were performed using a commercially available 2- to 4-MHz transducer (Sonos 5500, Philips, Andover, MA, USA) at baseline, at early follow-up (mean 26±13 days after the operation, range 11–55 days), and annually thereafter (last follow-up with a mean of 33±14 months after the operation) for measurement of cardiac function and dimensions, estimation of pulmonary artery pressure, and assessment of the degree of valvular regurgitation. The severity of regurgitation was classified as none (0), trivial (1+), mild (2+), moderate (3+), or severe (4+), depending on how far beyond the mitral or tricuspid valve the regurgitation extended into the atrium. The left-ventricular (LV) end-diastolic dimension, LV end-systolic dimension, and left-atrial dimension were determined from two-dimensional TTE images in the parasternal long-axis view. The LV ejection fraction was calculated by means of Simpson's method with two apical views. M-mode measurements were performed according to the recommendations of the American Society of Echocardiography. All preoperative echocardiographic findings and other parameters were reviewed in a blinded fashion.
2.2 Surgical procedure
Surgical intervention was performed through a median sternotomy under a standard cardiopulmonary bypass using bicaval drainage with intermittent cold-blood cardioplegia. We applied the modified Cox III procedure for all patients with valvular AF, using bipolar saline-irrigated radiofrequency (Medtronic Cardioblate System; Medtronic Inc, Minneapolis, MN, USA). Briefly, two encircling lesions around the ostia of the pulmonary veins were made in an epicardial manner, using a bipolar device. Snares previously placed around the inferior and superior vena cavae were tightened, and an incision was made at the right-atrial free wall. Next, an endocardial lesion connecting the right-atrial incision to the tricuspid annulus was made using a bipolar device. A bipolar clamp was placed from the inferior aspect of the right atriotomy to the superior vena cava, while avoiding sinus node damage, then rotated and extended in a similar manner onto the inferior vena cava. After aortic cross-clamping, the mitral valve was exposed through the conventional right-sided left atriotomy, and a bipolar device was applied to create two connecting lesions from the incision toward the mitral annulus posterior portion and the left pulmonary veins. The unipolar saline-irrigated radio frequency (Medtronic Cardioblate surgical ablation pen; Medtronic Inc, Minneapolis, MN, USA) was then applied at the posterior annulus of the mitral valve and to make a connecting lesion from the left pulmonary veins toward the orifice of the left-atrial appendage. Finally, the atrial septum was ablated on both left- and right-atrial endocardial surface from both atrial incisions toward the fossa ovalis, using the bipolar device. The left-atrial appendage was oversewn using a running monofilament suture.
Subsequently, a mitral valve repair or replacement procedure was performed. Tricuspid annuloplasty was routinely performed for patients with moderate or severe tricuspid regurgitation (TR) or a dilated annulus. All surgical data are presented in Table 1.
2.3 Intra-operative tissue handling and histology examination
Samples of the right-atrial appendage were always obtained prior to commencement of the cardiopulmonary bypass, and left-atrial samplings were taken from the myocardium at the left-atrial posterior wall between the inferior and superior right pulmonary veins (adjacent to the atriotomy line) before forming the radiofrequency ablation lines. Atrial samples were fixed in 10% buffered formalin solution for 24–48h and embedded in paraffin blocks. The blocks were then cut into 4-μm sections and stained with hematoxylin and eosin (HE) and Masson trichrome. Slides were examined independently by two observers, blinded concerning which patients had recovered sinus rhythm.
2.3.1 Quantification of cell size (μm)
Atrial cell size was measured with HE staining. The short diameter of the cardiomyocytes was measured at the nuclear level in 50 cells randomly selected from five photomicrographs at 200× magnification. The diameters of 50 cells per sample were used to calculate the mean cell diameter.
2.3.2 Quantification of tissue fibrosis (%)
Quantitative measurements of fibrosis areas were performed with the assistance of an Image Processor for Analytical Pathology (IPAP, Sumika Technoservice Co., Hyogo, Japan) to determine the amount of fibrosis, which appeared in blue with Masson trichrome stain (Fig. 1 ). We defined the extent of fibrosis in each field as the ratio of myocardium to fibrotic area, which was calculated using the following formula: % fibrosis=(area of fibrosis/total tissue area)×100. The calculations were based on average measurements from five photomicrographs at 100× magnification.
The fibrotic area appeared as blue when stained with Masson trichrome stain (A). Quantitative measurement of fibrosis area was performed by summing the amount of areas stained in blue (B), with the assistance of an image analyzer: IPAP (Image Processor for Analytical Pathology, Sumika Technoservice Co., Hyogo, Japan). In this example, % fibrosis area was calculated as 14.8%.
2.4 Statistical analysis
Continuous variables are expressed as the mean±standard deviation (SD). Normally distributed variables were compared using Student's t-test for paired or unpaired data, and nonnormally distributed variables were compared by the Wilcoxon signed-rank test or the Mann–Whitney U test. Categorical variables were compared using chi-square analysis and Fisher's exact test. The echocardiographic variables over time were compared using repeated-measures analysis of variance, followed by paired t-test for individual significant differences. Correlations between variables were tested with Spearman's rank correlation analysis. Univariate analysis of the correlates with an unsuccessful maze operation was performed using logistic regression analysis. Factors showing a p value of less than 0.1 were then entered appropriately in a multivariate fashion. The results are summarized as odds ratio and 95% confidence intervals (CIs). A p value less than 0.05 was considered to be statistically significant. Statistical analyses were performed using JMP 7.0 (SAS Institute, Cary, NC, USA).
3 Results
3.1 Patient characteristics
Patients with chronic AF had a larger cardiothoracic ratio (63±7% vs 55±6%, p<0.01), larger left-atrial dimension (52±9mm vs 42±6mm, p<0.01), and higher degree of TR (2.3±1.0mm vs 1.7±0.6mm, p=0.02) as compared with those with normal sinus rhythm at baseline. There were no statistical differences for the other clinical parameters between patients with or without preoperative AF. Nearly half of the patients had a history of hypertension (48.9%). Procedures for the mitral valve were performed due to myxomatous degeneration in 24 patients (51.1%), rheumatic heart disease in 9 (19.1%), and ischemia-dependent MVD in 14 (29.8%), with mitral valve repair performed in 30 (63.8%), and mitral valve replacement in 17 (36.2%). There were no statistical differences concerning preoperative medications, co-morbidities, etiology of MVD, or surgical procedures, including the type of mitral valve surgery and frequency of concomitant surgical intervention between the groups.
Patients in the unsuccessful maze group also had a larger cardiothoracic ratio and larger left-atrial dimension as compared with those in the successful maze group (Table 1). The former group also tended to have a longer duration of AF and higher degree of TR, though the differences were not significant. There were no differences for the other clinical parameters between the successful and unsuccessful maze groups.
3.2 Surgical outcome
There were no operative mortalities. Intra-operative transesophageal echocardiography showed no evidence of residual mitral regurgitation (MR) in all patients, and there were no complications associated with the tissue sampling. During the follow-up with a mean period of 37±13 months, no patient required a redo operation for prosthetic valve dysfunction or MR recurrence. Three of 24 patients, who underwent the maze operation, required implantation of a dual-mode permanent pacemaker (DDD) at 2, 7, and 34 months after the operation, respectively.
Serial echocardiographic results for patients with preoperative AF according to the successful and unsuccessful groups are summarized in Table 2 . In both groups, the left-atrial dimension decreased early postoperatively in parallel with improvement in MR. During the late follow-up period, no further significant change in degree of MR was seen in either group, and the left-atrial dimension remained stable in the successful maze group, whereas it increased again in the unsuccessful group. As a result, the mean values for left-atrial dimension in the unsuccessful maze group were significantly larger than those in the successful group at all follow-up time points.
Serial echocardiographic results in patients with valvular AF.
In the successful maze group, early postoperative TR grade was significantly improved, which was sustained up to the late follow-up period in association with decreased pulmonary artery pressure. By contrast, in the unsuccessful maze group, TR grade remained unchanged in the early postoperative period, and then tended to worsen during the late follow-up period, which was associated with higher pulmonary artery pressure as compared with the successful group. There were no differences in serial changes of TR grade between patients, who did and did not undergo tricuspid annuloplasty.
3.3 Histological findings (Table 3, (Fig. 2 and (Fig. 3)
In the left and right atria of 47 patients with MVD, the mean atrial cell sizes were 16.5±5.0μm and 14.7±4.6μm, while intracellular fibroses were 11.4±7.8% and 10.8±6.7%, respectively. Patients with preoperative AF had larger atrial cell sizes (19.0±5.0μm vs 13.9±3.5μm in the left atrium and 17.0±4.8μm vs 12.3±2.8μm in the right atrium, p<0.01, respectively) and a larger amount of intercellular fibrosis (15.8±8.8% vs 6.9±2.4% in the left atrium and 15.2±6.2% vs 6.2±2.9% in the right atrium, p<0.01, respectively) in both atria as compared with those with preoperative sinus rhythm. There were 5.1μm (CI: 2.6–7.7) and 4.7μm (CI: 2.4–7.0) differences (effect size) in left- and right-atrial cell sizes, while 8.9% (CI: 5.1–12.7) and 9.1% (CI: 6.2–11.9) differences (effect size) in left- and right-atrial fibrosis between the groups, respectively. Also for patients with preoperative AF, those in the unsuccessful maze group had significantly larger atrial cell sizes and a larger amount of intercellular fibrosis in the left atrium as compared with those in the successful group, whereas there were no significant differences with regard to the histological features of the right-atrial appendages between the groups. There were 6.8-μm (CI: 3.3–10.3) differences (effect size) in left-atrial cell sizes, while 13.9% (CI: 8.6–19.1) differences (effect size) in left-atrial fibrosis between the groups, respectively. When we compared histological features between right and left atria, there were no differences between them in the successful maze group or in patients with preoperative sinus rhythm. However, a larger amount of left-atrial intercellular fibrosis as compared with the right atrium was confirmed in the unsuccessful maze group.
Microscopic findings of cellular hypertrophy from patients with MVS and sinus rhythm (A), MVS and AF in successful maze group (B), and MVS and AF in unsuccessful maze group (C). Microscopic findings of atrial intercellular fibrosis from patients with MVS and sinus rhythm (D), MVS and AF in successful maze group (E), and MVS and AF in unsuccessful maze group (F). MVS: mitral valve surgery; and AF: atrial fibrillation.
Boxplots of atrial fibrosis (A) and atrial cell sizes (B) in patients with MVS and sinus rhythm (white bars), MVS and AF in the successful maze group (light gray bars), or MVS and AF in the unsuccessful maze group (dark gray bars). Asterisks indicate p values less than 0.01. MVS: mitral valve surgery; AF: atrial fibrillation; and NS: not significant.
Histopathological changes in left and right atria.
Clinical or histological factors correlated with unsuccessful maze operation for valvular AF.
As for the underlying etiology of MVD, patients with mitral stenosis (n=9) tended to have more extensive intercellular fibrosis in both atria as compared with those with MR (n=38), though the difference was not significant (15.4±11.2% vs 10.5±6.7% in the left atrium and 14.1±6.4% vs 10.0±6.6% in the right atrium, p=0.09, respectively). When we compared the three different etiologies, patients with a rheumatic etiology (n=9) had more extensive intercellular fibrosis in the left atrium as compared with those with cardiomyopathy (n=14), or myxomatous degeneration (n=24) (15.4±11.2% vs 13.5±7.1% vs 8.7±5.8%, p=0.04).
3.4 Correlations between clinical and histological factors and unsuccessful maze operation (Table 4)
Univariate analysis revealed that larger left-atrial dimension, larger amount of left-atrial fibrosis (>15%), and larger cell sizes in the left atrium were significantly associated with an unsuccessful maze operation in patients with valvular AF. Furthermore, multivariate analysis identified a larger amount of left-atrial fibrosis (>15%) as a significant correlate with an unsuccessful maze operation.
3.5 Correlations between histological changes in patients with mitral valve disease and clinical features
No correlation was found between the histological features concerning both atria and age, sex and cardiothoracic ratio. Preoperative left-atrial dimension was positively correlated with atrial cell size (r=0.656, p<0.01 in the left atrium and r=0.266, p=0.07 in the right atrium) and the amount of atrial fibrosis (r=0.677, p<0.01 in the left atrium and r=0.515, p<0.01 in the right atrium). In patients with preoperative AF, duration of AF was positively correlated with the amount of left-atrial fibrosis (r=0.516, p<0.01 in the left atrium and r=0.358, p=0.09 in the right atrium), but not with cell sizes in both atria.
Interestingly, the degree of preoperative TR was positively associated with atrial histological features in the right atrium, but not with those in the left atrium (Table 5). Furthermore, the estimated pulmonary artery pressure at baseline was positively correlated with right-atrial intercellular fibrosis (r=0.297, p=0.02).
Histopathological changes according to the grade of TR.
4 Discussion
The results of the present study suggested that patients with MVD and preoperative AF had extensive atrial structural changes as compared with those with MVD and preoperative sinus rhythm, which were consistent with previous investigations [8, 12]. Among the patients with preoperative AF, left-atrial histological features such as fibrosis and dilatation were more extensive in the unsuccessful maze group as compared with the successful maze group. Importantly, we found that a larger amount of fibrosis in the left atrium, but not in the right, was significantly associated with an unsuccessful maze operation for patients with valvular AF. Our results are similar to the previous investigation by Saito and colleagues [13], who investigated the relationships between histopathological features in the left-atrial appendages and postoperative recurrence of AF in patients with valvular AF. Other previous studies also suggested that fibrosis might be an important factor in the maintenance and progression of AF, on the basis of cell–cell decoupling and isolation of myocytes caused by fibrosis [8, 14], which was consistent with our histological findings in the unsuccessful maze group. Saito and colleagues also suggested that multiple micro-reentries, which were difficult to block with a maze operation, were produced when severe fibrosis extended into intercellular space and separated individual cardiomyocytes [13]. Notably, a larger amount of left-atrial intercellular fibrosis as compared with the right atrium was seen only in the unsuccessful maze group. These results suggest the importance of investigating the left atrium for predicting an unsuccessful maze operation, as it is well known that the initiation and perpetuation of AF pathophysiologically depends on the left atrium [15].
The present study did not find a clear correlation between structural changes in the right-atrial appendage and an unsuccessful maze operation. However, extensive structural features in the right-atrial appendages were seen in patients with MVD and AF as compared with those with MVD and sinus rhythm, suggesting that the initiation of AF might promote fibrosis and cell dilatation in both atria. Interestingly, we found that the severity of preoperative degree of TR was positively associated with right-atrial histological changes. Thus, we speculate that more extensive structural changes in the right atrium can dilate the right atrium as well as the annulus of the tricuspid valve, resulting in a higher degree of TR in patients with AF as compared with those with sinus rhythm. Additional investigation is necessary to confirm the clinical implication of the histological features in the right-atrial appendages.
The morphological features of the atrial tissues from patients with MVD and AF can be attributed to valvular heart disease, AF, or both. We also analyzed the influence of MVD itself, without, AF on right-atrial structural remodeling. During the same period as this study, we also examined right-atrial appendages obtained from 19 patients without a history of AF or MVD, who underwent open-heart surgery for thoracic aortic aneurysms. There were no differences concerning structural features of the right-atrial appendages between patients with (n =23) and without (n =19) MVD and normal sinus rhythm (cell sizes; 12.3±2.8μm vs 12.8±2.5μm, % fibrosis; 6.2±2.9% vs 5.0±2.1%, p =NS), which suggests that MVD alone without AF does not necessarily promote structural changes in the right atrium. Together, our results indicate that initiation of AF associated with MVD mainly causes progression of structural remodeling in the right atrium rather than MVD alone.
Because of the nature of our study, we could not determine whether cardiomyocytes were able to return to a normal phenotype after restoration of normal sinus rhythm or whether a point of no return existed. The reversibility of AF-induced structural changes has proven to be a very slow process that takes at least several months, and some structural changes may even be irreversible [9]. In the present study, 16 patients with a successful maze group had maintained sinus rhythm after surgery from 19 to 54 months (mean 42±9 months). Moreover, our echocardiographic findings demonstrated that the left-atrial dimension decreased postoperatively and remained stable in parallel with improvement in MR in the successful maze group. We speculate that this left-atrial reverse remodeling may be associated with possible reversibility of structural remodeling after successful restoration of sinus rhythm, contributing to the maintenance of normal sinus rhythm for a long period. By contrast, in the unsuccessful maze group, left-atrial dimension decreased postoperatively, but increased again without any evidence of deterioration of MR during the late follow-up period. This result suggested that persistent AF associated with advanced intercellular matrix remodeling might cause left-atrial remodeling (enlargement) as well as the reduction of left-atrial compliance, independent of left-atrial pressure, which could be decreased by elimination of MR. However, an additional animal study is necessary to elucidate the reversibility of atrial structural changes and negative impact of persistent AF on atrial structural remodeling.
Serial echocardiographic studies showed that postoperative deterioration (progression) of TR occurred in 75.0% (6 of 8) and 12.5% (2 of 16) of the patients in the unsuccessful and successful maze groups, respectively (p=0.09). This result was similar to the previous investigation by Stulak and colleagues [16], who compared degree of postoperative TR between patients who underwent a concomitant maze operation combined with MVS and had restored normal sinus rhythm and case-matched control patients who underwent MVS alone and remained in AF. They suggested that performance of the maze procedure was the most significant predictor of halting the progression of TR in patients undergoing MVS and a concomitant maze operation. Matsuyama and colleagues also identified several factors that were predictive of late TR after MVS, including preoperative TR of 2+, persistent AF, and an enlarged left atrium [17]. In the present study, there was no difference in the proportion of patients, who presented preoperative TR of 2+ between patients in the successful and unsuccessful maze groups. However, it was not surprising that TR worsened in the unsuccessful maze group, as those patients harbored two significant risk factors for the development of late TR after MVS.
The renin–angiotensin system has been shown to be involved in atrial structural remodeling due to AF [12]. The study of Goette and colleagues found increased expressions of the angiotensin-converting enzyme (ACE) and angiotensin II-dependent signal transduction pathway activated in atrial tissues of patients with AF [18]. Recently, the ACE-inhibitor and/or angiotensin II receptor blockers (ARBs) were shown to attenuate atrial fibrosis and conduction abnormalities in animal models [19–21]. In the present study, 31 patients who received preoperative ACE-inhibitor and/or ARB had less atrial fibrosis as compared with 16 patients without those drugs (8.8±5.4% vs 13.9±9.2% in the left atrium, p=0.02 and 9.0±6.0% vs 12.6±7.0% in the right atrium, p=0.06). Furthermore, in patients with AF, 88% (15 of 17) of patients with preoperative ACE-inhibitor and/or ARB administration had restored sinus rhythm, as compared with only 14% (1 of 7) of those without administration of such drugs (p=0.08). To improve the outcomes of a maze operation for valvular AF, it is important to prevent structural remodeling caused by AF itself, as the persistent high susceptibility to AF might be due to structural remodeling of the atria as a result of prolonged AF [9].
5 Limitations
There are several potential limitations, including the small number of patients in this study. Certainly, further studies with more patients enrolled are necessary to confirm our results. Second, the atrial tissues removed during the operation may not be representative of the atrium as a whole. However, an atrial biopsy from other sites is invasive, and the procedure itself may result in atrial irritation. Corradi and colleagues [22] evaluated regional left-atrial interstitial remodeling in patients with chronic AF undergoing MVS, and suggested that the left-atrial free wall around the pulmonary vein ostia was a region characterized by marked interstitial remodeling as compared with the left-atrial appendage. We agree with their suggestion that the left-atrial tissue around the pulmonary vein ostia might be a morphologically appropriate target for ablation treatment aimed at sinus rhythm restoration. Third, we did not analyze atrial structural changes in patients with paroxysmal AF. However, previous investigations have suggested that there is no significant difference between paroxysmal and chronic AF regarding changes in the extracellular matrix components [8, 18]. Finally, we did not investigate the related signal pathways, including the renin–angiotensin system, matrix metalloproteinases (MMPs), or tissue inhibitors of MMP in patients with valvular AF. Additional studies are necessary to confirm the impact of MVD with or without AF on atrial structural remodeling.
6 Conclusion
The present results indicate that a larger amount of fibrosis in the left atrium, but not in the right atrium, is significantly associated with an unsuccessful maze operation for patients with valvular AF. New strategies for improving the outcome of this procedure will depend on a better understanding of the mechanisms underlying atrial structural remodeling.
Presented at the 24th Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 11–15, 2010.
Acknowledgments
We are grateful to Dr Kazuo Abe for his excellent anesthetic management and Mr Masakazu Ueda for assistance with echocardiographic and pathological data collection. We also thank Mr Hiroyuki Waki and Mr Takashi Daimon for their excellent comments and suggestions for statistical analysis, and Mr Yoshifumi Chazono for technical assistance with the IPAP image analyzer.
Conference discussion
Dr N. Doll (Stuttgart, Germany): This excellent study gives us one more little piece of the mosaic to understand why we fail in our maze procedures.
You could show that there is a group with an amount of fibrosis more than 15% in patients with rheumatic heart disease. My first question is: have your findings influenced your daily work, would you say? In those patients with an estimated amount of fibrosis more than 15%, would you still perform the maze procedure, or not?
And on the other hand (I think you didn’t mention, but I read it in your manuscript), you could show that patients receiving ACE-inhibitors preoperatively had a much better outcome. Could there be a recommendation from your study that every patient with atrial fibrillation could take ACE-inhibitors prior to surgery?
And my last point is, you said there is reverse remodeling which takes a lot of time, and we know that the left-atrial diameter will decrease over time. And you said in your conclusion that we need an animal model, a chronic animal model, to show the reverse remodeling process after restoring sinus rhythm. And my question is: what would be the best animal model for this approach?
Dr Kainuma: I would like to answer the first question. My answer is yes, our strategy in regard to the maze operation for valvular AF should be changed from this study. We should select appropriate patients who benefit from the maze operation.
The second question, this study clearly shows that prevention of structural remodeling in the left atrium is an important element in improving the outcome of the maze operation in valvular AF. Activation of the renin–angiotensin system causes atrial cell growth, proliferation of fibroblasts and atrial fibrosis. In a recent study of a canine model, the medications including the ACE-inhibitor or ARB were shown to attenuate left-atrial fibrosis or conduction abnormality. In the present study, 31 patients who received preoperative ACE-inhibitor or ARB had less atrial fibrosis in both atria as compared to 16 patients without those drugs. So I think that preoperative medication with those drugs should be performed in patients who undergo the maze operation when there is no contraindication.
Dr W. Wang (San Diego, USA): One question. How do you obtain your specimen from the left atrium? Is it from multi points, multicenter, or just one point?
Dr Kainuma: We obtained the left-atrial tissues from one point on the posterior wall. As you comment, I agree that it is an important limitation of this study. But the previous study showed a distribution of the amount of fibrosis in the left atrium, and the left-atrial posterior wall was a region characterized by marked interstitial remodeling. So we chose to obtain the left-atrial tissue at the posterior wall which was believed to be related to the occurrence or maintenance of AF and the important target for treatment of AF.
Dr C. Vicol (Munich, Germany): I just question one of your conclusions. I think that rather than exclude patients off the VAD, you just reinforce the importance of follow-up and very aggressive treatment to restore sinus rhythm during follow-up. And I think we, as surgeons, should shift from the mode of discharging patients home and just monitor the success or failure, and create the very strict algorithms of antiarrhythmic drugs and cardioversions in order to help to reverse remodeling to occur as maximally as it can. I wouldn’t exclude patients based on the assumption that they have severe fibrosis.
Dr A. Diegeler (Bad Neustadt, Germany): Did you have a chance to look with MR on these patients and could you correlate MR findings with the fibrosis?
Dr Kainuma: We have not evaluated that issue in this study.
Dr N. Moat (London, United Kingdom): Could I just ask you briefly. I may have missed it in your talk. Are these all rheumatic patients or a mixture of rheumatic and degenerative disease?
Do these patients all have rheumatic valvular disease or are they a mixture of rheumatic and degenerative disease?
Dr Kainuma: The mitral valve etiology?
Dr Moat: The patients have mitral valve disease. Do they all have rheumatic disease or degenerative disease?
Dr Kainuma: Sorry, I could not catch that.
Dr Doll: There were nine patients with rheumatic etiology, and 24 patients had myxomatous degeneration. And he could show really significant differences between the rheumatic and the myxomatous. And that's a really good conclusion then.
Dr Moat: That's what I was waiting for. So there was more fibrosis in the rheumatic?
Dr Doll. Yes, much more.
