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J Thorac Cardiovasc Surg 2006;131:1364-1372
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Relationship between atrial histopathology and atrial fibrillation after coronary bypass surgery

Giovanni Mariscalco, MD a , * , Karl Gunnar Engström, MD, PhD, FRCS b , Sandro Ferrarese, MD a , Giuseppe Cozzi, MD a , Vito Domenico Bruno a , Fausto Sessa, MD c , Andrea Sala, MD a

a Department of Surgical Sciences, Cardiac Surgery Division, Varese University Hospital, University of Insubria, Varese, Italy
c Department of Human Morphology, Pathology Division, Varese University Hospital, University of Insubria, Varese, Italy
b Department of Surgical and Perioperative Sciences, Heart Center, Cardiothoracic Division, Umeå University Hospital, Umeå, Sweden.

Received for publication October 16, 2005; revisions received December 18, 2005; accepted for publication January 30, 2006.

* Address for reprints: Giovanni Mariscalco, MD, Department of Surgical Sciences, Cardiothoracic Division, Varese University Hospital, I-21100, Varese, Italy (Email: giovannimariscalco{at}yahoo.it).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
BACKGROUND: Postoperative atrial fibrillation is common after coronary surgery. The cellular condition of atrial myocytes might play a part in the postoperative development of atrial fibrillation. Our study aimed to investigate whether patients in whom postoperative atrial fibrillation develops show pre-existent alterations in histopathology of the right atrium and how such changes are expressed in relation to the use of cardiopulmonary bypass.

METHODS: Seventy patients undergoing elective coronary revascularization were prospectively randomized to on-pump conventional surgery (conventional coronary artery bypass grafting, n = 35) or off-pump surgery on the beating heart (off-pump coronary artery bypass grafting, n = 35). Samples from the right atrial appendage were immediately collected after opening the pericardium. In the on-pump group samples were also taken after weaning from cardiopulmonary bypass. Focusing on degenerative alterations, histology was studied by means of light microscopy and for confirmation of particular findings by means of electronic microscopy.

RESULTS: Twenty-two (31%) patients had postoperative atrial fibrillation, with the rate not being different between the off-pump coronary artery bypass grafting and conventional coronary artery bypass grafting groups (P = .797). Left atrial enlargement and inotropic requirement were related to atrial fibrillation. Interstitial fibrosis, vacuolization, and nuclear derangement of myocytes were the histologic abnormalities associated with the development of postoperative atrial fibrillation. However, in multivariate analysis fibrosis was confounded by myocyte vacuolization (P = .002) and nuclear derangement (P = .016), representing independent atrial fibrillation predictors. As expected, the conventional coronary artery bypass grafting and off-pump coronary artery bypass grafting groups showed similar histology, but more importantly, no atrial changes were detected in relation to cardiopulmonary bypass exposure in the conventional coronary artery bypass grafting group. Atrial histology showed degenerative changes that correlated with advanced age and left atrial enlargement.

CONCLUSIONS: Our study supports the contention that atrial fibrillation after coronary surgery is associated with pre-existing histopathologic changes of the right atrium. Patients randomly allocated to off-pump coronary artery bypass grafting procedures showed a similar rate of atrial fibrillation and a similar relationship to atrial histology as did those exposed to cardiopulmonary bypass. Cardiopulmonary bypass did not cause additional changes in tested histology variables.

Abbreviations and Acronyms AF = atrial fibrillation; CABG = coronary artery bypass grafting; cCABG = conventional coronary artery bypass grafting; CPB = cardiopulmonary bypass; OPCAB = off-pump coronary artery bypass grafting


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 

Figure 1
Dr Mariscalco


Postoperative atrial fibrillation (AF) is a common and perplexing problem after coronary artery bypass grafting (CABG). AF is associated with increased mortality and morbidity 1,2 Go and with accompanying longer and more costly hospitalizations. 1,3 Go Although several studies have identified various baseline predictors of postoperative AF, the pathophysiology remains unclear. 4 Go Prevention and treatment are also controversial issues. 4 Go The use of cardiopulmonary bypass (CPB) has been postulated as being a main AF-explanatory variable in relation to myocardial ischemia, 5 Go inflammatory response of CPB itself, 6 Go and the adverse effects of cardioplegia. 7 Go In recent years, off-pump CABG (OPCAB) has emerged as a possible solution to this problem. However, there is evidence to suggest that patients vulnerable to postoperative AF have a pre-existing electrophysiologic abnormality, 8 Go altered myocyte histology, 9-13 Go or both, justifying why some patients experience AF and others do not.

Our aim was to identify which pre-existent histopathologic alteration is predictive of postoperative AF when superimposed on the surgical stress of coronary surgery and when randomized to being performed with and without CPB.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Population
Over a 2-year period, 70 patients scheduled for primary and isolated elective coronary artery bypass surgery were prospectively randomized for coronary revascularization with either on-pump conventional surgical intervention (cCABG group, n = 35) or off-pump surgical intervention (OPCAB group, n = 35). Inclusion required preoperative sinus rhythm without clinical evidence of hemodynamic or electrophysiologic dysfunction of the right atrium. All enrolled patients had a normal P-wave morphology and right atrial pressure. Exclusion criteria encountered were history of supraventricular arrhythmias, presence of a pacemaker device, infection within 6 weeks preceding the operation, inflammatory disorders, or immunosuppressive therapy. The study cohort contained 57 men and 13 women (age range, 46-80 years; Table 1).


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  		TABLE 1. Clinical data of the patients, with subdivision into groups based on type of operation
 
All patients had undergone preoperative coronary angiography, and transthoracic echocardiography was used to measure left atrial size along the anteroposterior diameter, left ventricular function, and right atrial pressure. 14,15 Go Preoperative medications, including ß-blockers, diuretics, antihypertensives, and calcium-channel blockers, were routinely omitted on the day of the operation and restarted after the operation unless clinically contraindicated.

Specimens of the right atrial appendage were collected after opening of the pericardium and in the cCABG group, with an additional sample taken after weaning from CPB. The study received ethical committee approval for clinical trials, and all patients provided their consent to participate.

Surgical Management
The patients followed identical surgical and anesthetic protocols. CPB was of standardized fashion with ascending aortic and 2-stage venous cannulation of the right atrium at systemic moderate hypothermia (32°C). Myocardial protection was accomplished by means of antegrade intermittent cold blood cardioplegia. Off-pump procedures were performed at near normothermia (35°C). The left internal thoracic artery was routinely grafted to the left anterior descending artery, whereas the right internal thoracic artery and the saphenous vein were used for other target vessels. At the end of the operation, patients were taken to a dedicated cardiovascular intensive care unit and monitored for at least 24 hours.

AF Definition and Detection
All patients were monitored daily until discharge with continuous electrocardiographic telemetry, as well as standard 12-lead electrocardiography. Additional recordings were collected at clinical suspicion of AF. Only AF episodes lasting longer than 15 minutes were considered. Atrial flutter or tachycardia were disregarded because of their different mechanisms. 16 Go

Histologic Analysis and Definitions
Atrial samples were fixed in buffered formalin (formaldehyde, 4% wt/vol, and acetate buffer, 0.05 mol/L) for 12 hours at room temperature, followed by dehydration, embedding in paraffin, and cutting into 4-µm serial sections. Sections were stained with hematoxylin and eosin and Masson trichrome. Morphometric evaluation was conducted by a trained pathologist blinded to patient characteristics and AF occurrence. An Olympus BX40 light microscope (Olympus, Tokyo, Japan) was used. Pathology referring to atrial myocytes and connective tissue components were evaluated by using semiquantitative scales similar to that previously described by Ad and colleagues. 10 Go Assessment of atrial myocytes included the degree of vacuolization from loss of myofibrils. 17 Go Vacuolization was scored as 0 or 1 (0 = absent, 1 = observed at any rate). In specimens positive for vacuolization, the degree of myolysis was also evaluated on the basis of vacuole density and size, both scored from 1 to 3. The existence of hypertrophy and atrophy were rated from 0 to 2 (from absent to diffuse presence). Myocyte nuclear derangement encountered a composite evaluation of apoptotic pyknotic figures or necrotic nuclear changes, rated from 0 to 2. The presence of lipofuscin was also evaluated and rated from 0 to 3. The analysis of connective tissue components focused on interstitial edema (rated 0-3), mononuclear exudates (rated 0-2), fibrosis (rated 0-3), fibroelastosis (rated 0-2), and arteriolar hypertrophy (rated 0-1), respectively.

A small portion of each specimen was separated for electron microscopic observations. This analysis was performed on selected specimens in which light microscopy had shown varying degrees of myocyte vacuolization, nuclear derangement, and/or fibrosis. The ambition was to confirm light microscopic data, and electron microscopy was performed in 9 patients. Tissue samples were fixed for 2 hours at 4°C in a mixture of 2% paraformaldehyde and 2% glutaraldehyde in 0.05 mol/L (pH 7.3) cacodylate buffer, postfixed in 1% osmium tetroxide for 1 hour at room temperature, dehydrated in ethanol, and embedded in Epon-Araldite (Sigma-Aldrich, Chemie Schnelldorf, Germany). Ultrathin sections were stained with aqueous uranyl acetate for 25 minutes and Reynolds lead citrate for 20 minutes and examined with a Morgagni electron microscope (Philips, Eindhoven, Netherlands).

Data Analysis
Clinical and histopathologic data were prospectively recorded and tabulated with Microsoft Excel (Microsoft Corp, Redmond, Wash). The Fisher exact test, the {chi}2 test, the McNemar test, and logistic regression were used as appropriate for categoric variables, and a Student t test was applied for continuous variables. Stepwise multiple logistic regression was performed on variables with a P value of .05 or less at univariate analysis. Dichotomization is defined in the tables.

All data are presented as means ± standard deviation unless stated otherwise. Statistical analysis was computed with SPSS, release 13.0 for Windows (SPSS Inc, Chicago, Ill).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Clinical Results
Patient demographics, operative and postoperative characteristics of enrolled patients, and characteristics with randomization into pump modality are depicted in Table 1. The cCABG and OPCAB groups were comparable in all preoperative characteristics. None of the patients died. The overall incidence of AF was 31%, with 12 patients in the cCABG group and 10 in the off-pump group, representing a nonsignificant difference (P = .797). All patients affected by AF subsequently regained sinus rhythm. The median duration of AF was 4.6 hours (range, 1-48 hours). Of the patients with AF, 15 (68%) had arrhythmias within 48 hours after the operation. Recurrent postoperative AF was recorded in 6 of the affected patients.

Table 2 lists possible predictors of AF. The commonly agreed AF predictors (eg, age, chronic obstructive pulmonary disease, and pump modality) did not reach significance in this study. Significant findings in relation to AF were left atrial size (anteroposterior diameter, P = .008) and inotropic support requirement (P = .001, Table 2). Moreover, there was a positive correlation between left atrial diameter and age, suggesting a moderate explanatory relationship (r 2 = 0.140, P = .002, r = 0.370). No correlation was demonstrated between left atrial size and decreased left ventricular function (P = .806, r = .030).


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  		TABLE 2. Atrial fibrillation and key parameters for univariate predictors
 
Atrial Histology
An increased presence of myocyte vacuolization and interstitial fibrosis, both observed at a rate of 91%, was detected for patients with AF, which compared with 21% and 50%, respectively, for those remaining in sinus rhythm. Furthermore, an increased presence of myocyte nuclear derangement was found in patients with AF. Mean scores and univariate statistics are reported in Table 2. Figures 1 and 2 Go show typical examples of atrial histopathology by means of light and electron microscopy. When analyzed in multivariate mode, vacuolization and degree of myocyte nuclear derangement remained independent versus AF (P = .002 and P = .016, respectively), whereas fibrosis was confounded to an insignificant level by these variables (Table 3). In patients with observed myocyte vacuolization, the density and size of vacuoles both correlated univariately with AF occurrence (P = .002 and P < .001, respectively; data not shown in tables). Abnormal appearance was recorded for many of the other histology variables but with no statistical association to AF (Table 2).


Figure 1
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  		Figure 1. Photomicrographs of right atrial biopsy specimens. Different patterns of tissue morphology and cellular lesions are exemplified. A, B, and C, Mild-to-severe myofibrillar loss (vacuolization) on cross-section of right atrial tissue. Vacuolization is indicated by arrows. (A and B: hematoxylin and eosin stain, magnification 200x [A] and 400x [B]; C: Masson trichrome stain, magnification 400x.) D and E, Moderate-to-severe interstitial fibrosis. (D: hematoxylin and eosin stain, magnification 200x; E: Masson trichrome stain, magnification 200x.) Fibrosis is indicated by the letter F. F, Damaged myocyte appearance characterized by cytoplasmic eosinophilia and nuclear pyknotic derangement. Half-moon or sickle nuclei are indicated by arrows. (Hematoxylin and eosin stain, magnification 400x.)

 

Figure 2
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  		Figure 2. Electron microscopy of myocyte ultrastructure. A, Severe loss of myofibrils, which are replaced by vacuoles and mitochondria (indicated by asterisks and arrows, respectively; magnification 4400x). B, Hypercontracted myocyte expressing short sarcomeres (indicated by S), thickened Z lines, and nuclear shrinkage (indicated by N; magnification 3500x).

 

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  		TABLE 3. Multivariate analysis: Predictors of postoperative atrial fibrillation
 
Atrial histology was subdivided by randomization into cCABG and OPCAB groups. No differences between groups were detected for the baseline characteristics before CPB (Table 4). In the cCABG group atrial specimens after CPB were compared with those before CPB. However, no histologic difference was recorded with this comparison (Table 4). Univariate logistic regression was also performed to test the influence of selected intraoperative parameters on atrial histology. Aortic crossclamp time, CPB time, and cardioplegia dosage, as well as right coronary artery grafting, showed no such relationship (data not shown).


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  		TABLE 4. Histopathologic analysis of right atrial appendage tissue
 
The possible relationship between atrial histology and age was explored by using logistic regression. Age as a dependent variable selected hypertrophy, myocyte nuclear derangement, fibrosis, fibroelastosis, and, with borderline significance, vacuolization as explanatory factors (Table 5). A similar comparison was made versus left atrial diameter dichotomized at more than 37 mm. This analysis revealed vacuolization, the presence of myocyte nuclear derangement, and the severity of fibrosis as being related to left atrial size (Table 5). The possible effect of preoperative exposure to ß-blockers (n = 26) was tested in relation to atrial histology. However, no changes were discovered in relation to these drugs (data not shown).


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  		TABLE 5. Univariate analysis of age and left atrial diameter versus histology
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Despite several improvements in the surgical technique, AF still remains the most common complication after cardiac surgery. 4 Go Its incidence has paradoxically increased because the numbers of elderly patients suitable for surgical revascularization has steadily increased. 18 Go Mechanisms of AF pathophysiology have been subjected to intense investigation, but its exact determinants remain unclear. Several studies have reported conflicting results regarding the role of CPB and cardioplegic arrest in the development of AF after CABG and when compared with OPCAB procedures. 19-22 Go

Recent studies suggest that patients vulnerable to postoperative AF have pre-existing electrophysiologic alterations, possibly associated with cellular disturbances. 8-13 Go Myocyte vacuolization and apoptotic nuclear degeneration have been described in relation to postoperative AF for patients undergoing on-pump coronary surgery. 10-12 Go However, the effects exerted by the off-pump procedure on atrial histopathology have not been elucidated. Similar to previous findings, 10-12 Go our study revealed an association between preprocedural atrial histology and postoperative AF. No association or protective relationship versus OPCAB was found herein. Furthermore, right atrial histology was not significantly affected by CPB. A longer CPB time than necessary for routine CABG procedures might have changed this pattern.

Age is the only consistently reported risk factor of postoperative AF after cardiac surgery. Age-induced changes of the heart have been illuminated in some recent studies. 10-12,23,24 Go It has been proposed that atrial dilatation, together with hypertrophy and fibrosis, might promote re-entry arrhythmias. 25 Go Furthermore, loss of myocyte fibrils with fibrotic remodeling is proposed to interfere with cell-to-cell electrical coupling between atrial muscle fibers. 13,26 Go Our findings are in consonance with these suggestions. However, in a multivariate mode of analysis, atrial fibrosis was confounded by the more specific alterations of myocyte vacuolization and nuclear derangement. These findings are in consonance with the previous findings observed by Ad and colleagues 10,11 Go and Ak and associates. 12 Go Furthermore, myocyte hypertrophy was not found to be associated with AF in this study. It is noteworthy that age did not significantly relate to AF, a finding that must be viewed in perspectives of the limited number of studied patients. Nevertheless, advanced age was significantly related to atrial fibrosis and deranged myocyte nuclei. Left atrial enlargement showed a similar relationship to atrial histology. Atrial size was associated to both AF and age, which illustrated complex but important patterns of covariance. Results reported from both experimental and clinical studies suggest that increased wall tension or high frequency of beating, both being associated with atrial dilatation, might induce apoptotic myocyte death. 27,28 Go

In a recent study regarding AF, Ak and colleagues 12 Go reported an increased apoptotic pattern in vacuolized myocytes and suggested a "cause and effect" relationship between these variables. In our study myocyte vacuolization and deranged nuclear appearance coexisted but were independently found to be associated with AF. Myocyte vacuolization has been detected in conjunction with normal aging but also in response to hypoxia and ischemia. 23,24,29 Go Vacuolar changes might constitute a progressive cellular response to chronic ischemia. 29 Go It could be postulated that the onset of AF requires an initiating event, such as an acute injury or an intense neurological influence on the atria. 4,24 Go In addition, an underlying factor might be required for the onset and maintenance of the arrhythmia. 4 Go Superimposed on the age-related atrial changes are the effects of surgical trauma and pericardiotomy, in addition to adrenergic or chemical stimulation during perioperative support with catecholamines or other inotropic agents. 4,24 Go In the present study requirement of inotropic drugs was increased among patients who later had AF. The association between AF and inotropic requirement confirms previous reports, 21,30,31 Go often being interpreted as the influence of sympathetic activation by the drug. 4,16,30,31 Go However, the possibility that inotropic support reflects several preoperative conditions, such as decreased left ventricular function, as revealed in our study, or effects of aging must also be considered.

Investigation of AF mechanisms requires a large number of observations. Detailed microscopy of atrial samples limits such ambitions and restrains the statistical power. These circumstances might have explained the insignificant relationship of AF to the generally agreed predictors of age and chronic obstructive pulmonary disease. The same can be declared for the between-group comparison of the cCABG and OPCAB groups, although the numeric AF rate difference was minimal. In this study semiquantitative scores by a blinded observer were used for describing atrial histology. In view of the complex nature of cellular science, the search for numeric methods and key variables relating to AF is a major future aim. AF mechanisms are commonly referred to originate from the left atrium and pulmonary veins. 32 Go Despite this fact, practical and ethical considerations made us collect samples from the right atrium rather than from the left side, a limitation shared with many previous studies. 10-12 Go However, it is noteworthy how the right atrial appendage tissue has been recognized to mirror most of the pathologic alterations seen in chronic AF and for dilated cardiomyopathy. 29 Go Furthermore, routine histologic analysis is time consuming and does not allow for immediate and selective prophylactic treatment against postoperative AF. Studies are now required to explore the molecular events and gene expressions associated with increased AF susceptibility and possibly to identify useful treatment against such disorders.

In conclusion, our study supports the thesis that AF after coronary surgery is associated with pre-existing and degenerative changes of the right atrium, with a lower arrhythmic threshold when being superimposed by the surgical trauma. Patients randomly allocated to OPCAB procedures showed a similar rate of AF and a similar relationship to atrial histology as did those exposed to CPB. CPB as such did not cause additional changes in tested histologic variables.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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