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Ann Thorac Surg 2001;72:688-693
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Histologic atrial myolysis is associated with atrial fibrillation after cardiac operation

^a Department of Thoracic and Cardiovascular Surgery, Rabin Medical Center, Tel-Aviv, Israel
^b Department of Pathology, Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel
^c Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel

Address reprint requests to Dr Golomb, Department of Pathology, Sackler Medical School, Tel-Aviv University 69978, Israel
e-mail: egolomb{at}post.tau.ac.il

Presented at the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 
Background. Postoperative atrial fibrillation after cardiac operation is common. Despite the identification of risk factors associated with postoperative atrial fibrillation, the pathophysiologic mechanisms remain unclear. Myolysis has been recently described to be associated with maintenance of atrial fibrillation in experimental animals. In this study, we attempted to identify histopathologic changes in atria that might predict the development of postoperative atrial fibrillation, and specifically address its association with myolysis.

Methods. Right appendicular atrial tissue was sampled before and after cardiopulmonary bypass from 60 patients in sinus rhythm who underwent elective coronary artery bypass grafting.

Results. Fifteen patients (25%) developed postoperative atrial fibrillation. Histopathologic abnormalities were found in most patients (52 of 60). However, only myolysis and lipofuscin levels were found to be an independent histologic finding associated with the development of postoperative atrial fibrillation. Electron microscopy showed that myolytic vacuoles were not membrane bound, and were associated with lipofuscin deposits. Neither mitochondrial pathology nor apoptosis was detected in the atria before or after operation.

Conclusions. Abnormalities in biopsies before cardiopulmonary bypass can indicate the susceptibility to develop postoperative atrial fibrillation. This implies that the status of the atrium before cardiopulmonary bypass is a major determinant in the development of this common complication.

	Introduction

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Atrial fibrillation is a common complication in cardiac operation, occurring within the first week postoperatively in 20% to 40% of the patients undergoing coronary artery bypass grafting, and its incidence may be increasing [1]. Although postoperative atrial fibrillation is often regarded as a temporary innocuous problem, this complication has significant adverse effects: it increases the risk of cerebrovascular accident, and extends intensive care unit and hospital stay [2, 3]. The mechanism for the development of postoperative atrial fibrillation is unclear. It is known that postoperative atrial fibrillation involves reentry, resulting from dissimilar refractoriness between adjacent atrial areas [4], but the reason for these dissimilarities are unknown. Risk factors associated with the development of postoperative atrial fibrillation include advanced age, prolonged preoperative atrial conduction duration, chronic obstructive pulmonary disease, excess circulating catecholamines, electrolyte imbalance, atrial myocardial ischemia, sudden ß-blocker withdrawal, prolonged aortic cross-clamping time, and right atrial manipulation [1–7]. Despite the presence of one or more of these risk factors in nearly all patients, one of the confusing aspects of postoperative atrial fibrillation is the fact that it does not develop in roughly 60% of patients undergoing cardiac operation, indicating that some patients have an inherent preoperative risk and other patients do not. This may be specifically suggested by the findings that prolonged preoperative atrial conduction duration is associated with postoperative atrial fibrillation [6]. We previously showed preliminary data, indicating that high lipofuscin content and vacuolation in the atria may also be associated with vulnerability to postoperative atrial fibrillation [8]. Taken together, these factors indicate that the preoperative status of the patient and the atria are major determinants of the risk to develop postoperative atrial fibrillation, in addition to the stress and ischemia induced by the surgical procedure per se.

The association between advanced age and risk to develop atrial fibrillation after cardiac operation is striking, and specifically unclear. It has been attributed to age-related atrial changes such as atrophy and fibrosis [1, 9], but this association has never been directly examined.

Histopathologic examination of atrial tissue can identify different forms of mild, accumulating cellular injury: myolysis, fibrosis, fiber disarray, edema, and different forms of chronic inflammation. Furthermore, some of these changes are also encountered with advancing age in the normal atrium [9]. Susceptibility for postoperative atrial fibrillation depends on the preoperative metabolic status of the atria and this may be reflected in the histopathologic examination. The ischemic insult, the metabolic status, and aging of the cells may have morphologic consequences. The morphologic expression of the cellular status and insult may be correlated to the risk of initiating and maintaining atrial fibrillation in response to a given stimulus. Therefore, it is reasonable to hypothesize that if susceptibility to postoperative atrial fibrillation depends on the preoperative metabolic status of the atria, it could be predicted on the basis of morphologic parameters in preoperative histologic atrial specimens. The present study was designed to correlate any histologic finding in the atrial myocardium with the occurrence of postoperative atrial fibrillation, and thus identify markers for an increased vulnerability to developing atrial fibrillation after coronary artery bypass grafting.

	Material and methods

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Approval to conduct the study was obtained from the institution’s Investigative Review Board. Samples of right atrial appendage tissue were taken from 60 patients in normal sinus rhythm undergoing nonemergent coronary artery bypass grafting, before and immediately after weaning from cardiopulmonary bypass. The age of the patients ranged from 42 to 78 years (mean, 63 ± 9 years). Nine of the patients were women (15%).

Because the examination of atrial tissue is not routine to the pathologist, we developed a standard form-protocol for the examination of the atria (Table 1). Filling the form required a thorough examination of myocytes, connective tissue, and pericardium. In myocytes, the examination included the assessment of the degree of myolysis (loss of muscular striation and displacement of muscle content by cytoplasmic vacuoles), the existence of hypertrophy, atrophy, and muscle disarray, and the existence of apoptotic figures or necrotic cells. Myolysis severity score, mild to severe, combined the degree of the frequency and size of myolytic vacuoles and loss of striation. In the connective tissue, it required the examination and grading of interstitial edema, mononuclear exudates, fibrosis, fibroelastosis, and arteriolar hypertrophy. In the pericardium, it required the examination of the existence of mononuclear or fibrinous exudates, fibrinous pericarditis, and fibrous adherences. The form enabled a summarization of each histopathologic examination on a spreadsheet, and its correlation to postoperative events.

To determine whether intraoperative ischemia induced a cellular damage that can be assessed morphologically, we also stained serial sections by the Terminal deoxyUridine Nick End Labeling (TUNEL) assay, and by immunohistochemistry for hypoxia-induced factor-2. The TUNEL assay was done using a commercial kit (ApopTag, Oncor, Gaithersburg, MD) according to the manufacturer’s instructions. Counterstaining was carried out by methyl green. The TUNEL-stained specimens were thoroughly scanned to look for apoptotic nuclei. Three hundred to 1,000 nuclei were screened on each specimen, and the count of TUNEL-positive nuclei was recorded. Castrated rat prostate served as a positive control for the assay. Immunohistochemical staining for hypoxia-induced factor-2 was carried out using a commercially available antibody (Novus Biologicals), diluted 1:200.

All patients were monitored continuously after operation for the occurrence of atrial fibrillation until hospital discharge. Patients were considered to have postoperative atrial arrhythmias if interventional therapy (drugs or electrical cardioversion) was required to restore sinus rhythm.

The specimens were examined histologically by two independent investigators who were blinded as to which patients had developed postoperative atrial fibrillation. Electron microscopy was performed on selected specimens, with varying degrees of myolysis and fibrosis. Statistical analysis was assessed by correlating the association of multiple clinical and histologic variables with the occurrence of atrial fibrillation using logistic regression. Significant univariate predictors were entered into a multivariate analysis, and individually assessed for correlation using a two-tailed Pearson correlation test. A p value less than 0.05 was considered significant.

	Results

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Fifteen of the 60 patients in this study developed postoperative atrial fibrillation (25%), which occurred 12 to 144 hours after the operation. In-hospital mortality for these patients was zero.

No histologic differences were noted in atrial specimens before or after cardiopulmonary bypass, suggesting adequate myocardial preservation. Furthermore, hypoxia-induced factor-2 immunoreactivity was not detected in any of the specimens, before or after the operation.

The TUNEL assay did not reveal significant apoptotic endonuclease activity before or after the operation. TUNEL-positive nuclei were not a significant finding in any of the atrial specimens, before or after cardiopulmonary bypass. Only in 9 of the 120 slides a single TUNEL-positive nucleus was encountered, and we found two positive nuclei in only one slide. Therefore, special attention was given to specimens before cardiopulmonary bypass, with the assumption that some of the significant histopathologic changes may be already existing preoperatively.

Histologic abnormalities, defined as deviations from the classic definitions of normal atrial tissue, were observed in most specimens. Only 8 of the 60 patients had atria with no abnormality before cardiopulmonary bypass scored in the form protocol, or similar to those encountered in young healthy individuals. Some degree of myolysis was encountered in 48 of the 60 patients. Twenty patients exhibited moderate or severe myolysis, of whom 65% (13 patients) developed postoperative atrial fibrillation. When the examination was limited to patients with severe myolysis, a striking correlation between severe myolysis and atrial fibrillation was found: 10 patients showed severe myolysis of atrial myocytes (Fig 1C,F), nine of whom (90%) developed postoperative atrial fibrillation.

View larger version (176K): [in this window] [in a new window]   Fig 1. Photomicrographs of right auricular specimens of atrial tissue. Hematoxylin and eosin stain; magnification, x110 in A,C,E (general view); x440 in B,D,F (detailed view). (A, B) Normal atrium. (C, D) Atrium with fibrosis. (E, F) Atrium with myolytic perinuclear vacuoles.

View larger version (134K): [in this window] [in a new window]   Fig 2. Electron micrographs of atria with myolysis. The vacuoles are not membrane bound, filled with granular material, and contain lipofuscin particles, or are adjacent to the lipofuscin particles (A–C). Occasionally, two adjacent cells show a different density of contraction bands (C). Mitochondria are usually intact (D).

	Comment

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Recent reports have shown that postoperative atrial fibrillation constitutes a major clinical problem, and may lead to severe sequelae and high costs. Risk factors have been found and assist in identifying patients who are at a greater risk of developing this common complication [1–3]. However, until now, this knowledge has not been reflected in any treatment regimen, and all patients in a given institution get a similar pre and postoperative preventive antiarrhythmic treatment, irrespective of their risk to develop postoperative atrial fibrillation and with minimal success in reducing its incidence. A possible reason of this discrepancy is our lack of comprehension of the cellular and molecular mechanism of postoperative atrial fibrillation, and the susceptibility to develop it. Therefore, we cannot address a rational preventive treatment based on the risk. To have a better knowledge of the events in the atria that lead to atrial fibrillation after operation, the first step is to describe the atria before and after operation. In this study we took a primary observation of the atria in patients undergoing coronary artery bypass grafting, and described their atria.

The most powerful risk factor for the development of postoperative atrial fibrillation in most of the studies was age. It was argued that fibrosis and atrophy in the atria, which are characteristics of old age, contribute to the susceptibility to develop the complication [1, 9], but the link between these phenomena and atrial fibrillation after cardiac operation have not received scientific attention. In our study, we found significant fibrosis and atrophy in a significant portion of the patients (13 of 60 and 24 of 60 of the patients, respectively), but these were not associated with the development of atrial fibrillation postoperatively.

Another intriguing risk factor for postoperative atrial fibrillation is the increased signal average duration of the P-wave found in the preoperative electrocardiogram [6]. This risk factor indicates that the preoperative status of the atria may be a major determinant for the susceptibility to develop atrial fibrillation after operation and may explain to some extent why the performance of off-bypass coronary artery bypass grafting did not significantly reduce the number of patients having atrial fibrillation postoperatively. In our study, we evaluated the preoperative status of the atria morphologically. Despite the fact that all the patients were in sinus rhythm preoperatively, most of the atria showed different significant histopathologic abnormalities. Among these, the only abnormality that correlated with postoperative atrial fibrillation was the severity of the atrial myolysis. This suggests that myolysis reflects a chronic metabolic derangement in the atrial cells, which contributes to the development of atrial fibrillation. The association between myolytic vacuoles and lipofuscin further indicates that these vacuoles result from accumulating cellular damage.

In a preliminary report on histologic variables in the atrium, we reported on vacuolation and lipofuscin deposition as independent potential markers of susceptibility to atrial fibrillation [8]. The association between myolytic vacuoles and lipofuscin indicates that these are not independent variables, and myolysis also reflects deposition of lipofuscin. Furthermore, the lipofuscin pigment is concentrated and accentuated in the cytoplasm by the presence of myolysis, and cannot be considered an independent predictor.

In a recent study, Van der Welden and colleagues [10] induced atrial fibrillation in young, healthy goats, and studied its expression on connexins 40 and 43. They found that the maintenance of atrial fibrillation after pacing is associated with decreased levels and heterogeneous distribution of connexin 40 in the atrium. At the beginning of their experiment, young, healthy animals were resistant to the induction of atrial fibrillation. On the basis of their experiment, Tieleman and Crijns [11] pointed out that atrial myolysis induced by repeated arrhythmogenic stimuli was associated with maintenance of atrial fibrillation in the goats. In that study [11], myolysis was defined as loss of 10% of the myofibrillar structures. Myocyte vacuolation is a common aging-related phenomenon in people [9]. Our study clearly demonstrates that some people exhibit high degrees of atrial myolysis. This does not affect their basal rhythm, but when exposed to the insult of cardiac operation, these people have a higher tendency to develop postoperative atrial fibrillation.

Similar myolytic vacuolation of cardiac cells has been described in different conditions in humans. It occurs with normal aging in the atria in the sixth or seventh decade, but also occurs in response to hypoxia and ischemia [12–15]. Aime-Sempe and colleagues [16] described atrial myolytic vacuolation resulting from atrial fibrillation. In their study, severely damaged cells and apoptotic figures accompanied the myolytic vacuoles. However, in our study, in which all the patients were in normal sinus rhythm preoperatively, perinuclear vacuolation was not accompanied by signs of more severe damage to the myocytes.

Our study has obvious limitations. Its size is limited, and its major finding is based on the description of myolysis. It should be borne in mind that myolysis is a general, nonspecific finding. Studies are now required to dissect the molecular events and changes in gene expression that lead to the increased susceptibility. These may also enhance the identification of preoperative treatments that improve the preoperative metabolic status of the atrial cells, and reduce the risk for postoperative atrial fibrillation.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 
This study was supported by a grant from the Slezak Foundation for Heart Research. We thank Prof. Armand Abramovici for his helpful suggestions and assistance in examining the histologic specimens.

	Discussion

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DR LAWRENCE I. BONCHEK (Lancaster, PA): I enjoyed this very much. I am thinking about potential applicability to valve operation, if these sections can be analyzed rapidly enough. If you were to look at these in patients undergoing, for example, mitral valve grafting, it could influence your decision to perform a concomitant Cox/Maze procedure, because it might tell you something about the patients’s propensity to return to sinus rhythm or to retain sinus rhythm postoperatively. I wonder whether you have any plans to extend this work to patients with valvular heart disease, particularly mitral valve disease?

DR AD: Thank you for your excellent question. The decision whether to perform the Maze procedure in a combination with mitral valve operation is in my opinion not one that should be taken in the operating room. However, we are certainly looking into methods that will enable us to predict with high probability which patient is prone to develop postoperative atrial fibrillation. To achieve this we are trying to develop a test based on a frozen section that would correlate with our hematoxylin and eosin staining that was presented in this article. On the other hand, it will be much more feasible to have a test based on blood sample that could possibly correlate withthe pathology and the tendency of developing postoperative atrial fibrilation. To achieve this we are trying to develop a test based on a frozen section that would correlate with our hematoxylin and eosin staining that was presented in this article.

DR RALPH J. DAMIANO (St. Louis, MO): That was a beautiful presentation and very important work. I have several questions. First, what was the discriminatory power of your study? Although you did not find a lot of clinical and other histopathologic correlations, part of the problem may have been the small size of your study. How much of that may have just been a type II statistical error?

Second, some previous reports have associated the myolysis with increasing age. In your patient population did you quantify the degree of myolysis and was this correlated at all with patient age? Did you find a correlate with any clinical variable that might clue us into high risk groups?

And then finally, did the degree of myolysis correlate with any measurable electrophysiologic abnormalities in your patients?

DR AD: Thank you. With regard to your first question, I think that the weakness of the study is its sample size, and we were also surprised not to find any of the classic clinical risk factors such as advanced age as predictors for postoperative atrial fibrillation in this study. As far as correlation between any of the pathologic parameters such as myolysis and lipofuscin deposits and age, we did not find any. We believe that myolysis should be looked at with special attention especially when we link our findings with those from The Netherlands by Allessie’s and Tilman’s groups that showed that myolysis eased the ability to induce and maintain atrial fibrillation in the laboratory in a young goat model. Therefore we believe that the phenomenon of myolysis is telling us something about the condition of the atrial cells that should be farther investigated.

DR PAUL KURLANSKY (Miami, FL): It has been noted that intracellular calcium is correlated with atrial fibrillation. I was wondering if the milieu of myolysis may actually also be correlated with intracelular calcium such that the intracellular myolysis, for whatever reason, might provide an electrochemical substrate for the propagation of atrial fibrillation.

DR AD: I think that this is a very interesting point. The reason for my thought is that you probably noticed that there are some granules formations within the vicinity of the perinuclear vacuoles that we do not know the nature of. However, in our very basic staining it does not appear like calcium, but it may as well be, so as for now, I can not give you any hard data to support your assumption.

	References

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