a Department of Anesthesia and Perioperative Care, University of California, 521 Parnassus Avenue, San Francisco, CA 94143-0648, USA
b Department of Medicine, University of California, San Francisco, CA, USA
c Department of Cardiovascular Anesthesia, Kaiser Permanente Medical Center, San Francisco, CA, USA
Received March 24, 2004; revised June 14, 2004; accepted July 1, 2004 * Corresponding author. Tel.: +1 415 476 0711; fax: +1 415 502 2224 (E-mail: jmleung{at}itsa.ucsf.edu).
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Abstract |
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METHODS AND RESULTS: Three hundred patients undergoing elective coronary artery bypass graft surgery were monitored with intraoperative transoesophageal echocardiography to determine LA function and dimensions. Post-operative AF was monitored with continuous telemetry until hospital discharge. The relationship between clinical factors versus LA function and dimension was assessed using multi-variate logistic regression. By univariate analysis, patients who subsequently developed post-operative AF had a larger LA area and LA appendage area, and lower LA ejection fraction measured in the pre-bypass period compared to those without subsequent AF. By multivariable analysis, in addition to clinical data including age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.051.16, P<0.0001), body surface area (OR 13.31, 95% CI 1.8794.5, P=0.0097) and white race, post-bypass atrial systolic function (atrial filling fraction ⩽0.36, OR 2.51, 95% CI 1.036.13, P=0.04) and abnormal relaxation of the left ventricle (E duration 270 ms) (OR 2.89, 95% CI 1.346.24, P=0.0067) independently increased the risk of post-operative AF.
CONCLUSION: These results demonstrate that some of the structural and functional changes in the atria common to chronic AF in the elderly population are also prevalent in surgical patients who develop post-operative AF, suggesting that post-operative and chronic AF may have similar pathophysiology.
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Introduction |
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Similar to that occurring in the ventricle, accurate assessment of atrial dimensions and function is important for establishing the presence of atrial dysfunction. Global structural ventricular remodelling is the term used to describe a series of prototypical changes in cardiac structure that occur in response to injury or prolonged increase in cardiac load.11 These changes include an increase in chamber volumes and muscle mass and changes in the configuration of the left ventricle. Remodelling results in a deterioration in cardiac function and plays a major role in the progression of heart failure. Whether left atrial remodelling also occurs at the structural level, contributing to a decrement in atrial function and resulting in AF, as in left ventricular remodelling which contributes independently to the progression of heart failure12 may elucidate the pathophysiology of post-operative AF.
Previous epidemiological studies have suggested a strong relationship between ageing and AF in both the non-surgical and surgical population. Age-related changes in the atria may include atrial dilatation, hypertrophy and patchy fibrosis with destruction of the SA node.13 Therefore, measurements of both the geometry and function of the atria are crucial in understanding how age-related changes may impact on the development of AF. The function of the left atrium has typically been divided into three components: a reservoir, in which blood is collected and stored during ventricular systole; a conduit function, in which blood passes from the pulmonary veins to the left ventricle during passive ventricular filing in early diastole; and finally a booster function, in which the atrium contracts and augments the left ventricular filling at end-diastole.14,15 Left atrial dysfunction may be characterized by abnormality in one or more of these functions. Clinically, left atrial function can be measured using echocardiographic indexes.
Accordingly, our current study aimed to prove the hypothesis that patients who subsequently developed post-operative AF had pre-existent structural remodelling. When superimposed by the acute stress of surgical intervention, the atrium developed acute functional decline, manifested clinically as post-operative AF. This atrial function can be quantified non-invasively through the use of echocardiographic measurement of LA function and dimensions.
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Materials and methods |
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The sample size calculation was based on an estimated prevalence of post-operative AF of 30% based on our pilot study, and 80% power to be able to detect relative risks in the range of 1.62.0, significant at the 0.05 level.
Intraoperative management
Standard monitors for patients undergoing CABG surgery were used. These included 5-lead electrocardiography, radial and pulmonary arterial catheters and transoesophageal echocardiography (TEE). Intraoperative TEE was routinely performed and monitoring was continuous throughout the intraoperative period in patients undergoing open heart surgery at our institutions. Anaesthetic and surgical management of patients was not controlled and was per usual clinical practice. Cardiopulmonary bypass was conducted using a membrane oxygenator with haemodilution and mild systemic hypothermia.
Transoesophageal echocardiography
All patients had intraoperative TEE measurements performed before and after cardiopulmonary bypass. Echocardiographic measurements were obtained at end-expiration. All off-line echocardiographic analysis was performed using measurement programmes from the Tomtec/Freeland System (Broomfield, CO, USA). All analyses were based on the average obtained from measurements from two beats. Intra- and inter-observer variability was determined using similar methods reported in our previous work16 in which two study investigators repeated each measurements in 10 randomly chosen patients to ensure that a correlation coefficient of 0.9 or better was obtained by linear regression analysis.
Mitral inflow characteristics were analysed using Doppler echocardiography. Mitral inflow velocities were measured at end expiration at the level of the four-chamber view, at the tips of the mitral leaflets using pulsed Doppler, performed at end-expiration.17 The Doppler beam was aligned to produce the narrowest possible angle between the beam and the blood flow vector. The peak velocity during early filling (E), late filling from atrial contraction (A), the ratio of E/A, and the deceleration time from peak early filling extrapolated to the baseline were measured.
Pulmonary venous flow velocity and pulmonary vein diameter were recorded in the mid-oesophageal 4-chamber view with the sample volume placed within the proximal 2 cm of the left upper pulmonary vein. Colour Doppler was used to align the Doppler cursor parallel to the pulmonary venous flow. Filter and gain settings were adjusted to minimize noise. The peak systolic and diastolic velocities were recorded and the peak systolic/diastolic velocity ratio computed. The duration of the atrial reversed flow was also measured.
The left atrial (LA) area was determined by tracing the endocardium on a transverse mid-oesophageal short-axis view set at 3060°.10 Left atrial length was the average equidistant tracing from the mitral annulus to the LA posterior wall of the 4-chamber and the 2-chamber views. If the atrium was foreshortened by the echo field, the boundaries of the echo field were traced.
Left atrial appendage was imaged at the aortic short-axis view at 30°.18 Left atrial appendage peak velocity was measured by pulse wave Doppler, with the pulsed Doppler sample volume placed into the left atrial appendage cavity.
Left ventricular ejection fraction (LVEF) was measured at the mid-papillary, short-axis view. LVEF was calculated as: LVEF=(LVEDALVESA)/LVEDAx100% where EDA represents the end-diastolic area and ESA, the end-systolic area of the left ventricle.
Hepatic vein size and velocity was measured with pulsed wave Doppler at the level of the bicaval view.
Left atrial function
LA ejection fraction (LAEF) was calculated to estimate left atrial reservoir function:
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Haemodynamic data
Because changes in haemodynamic loading conditions may result in changes in echocardiographic measurements of left atrial and diastolic function, we also performed serial measurements of haemodynamics at the same time of the echocardiographic measurements. Heart rate, systemic, pulmonary artery and central venous pressures, as well as pulmonary capillary wedge pressure and thermodilution cardiac output were all measured during end-expiration during the pre- and post-bypass periods at the same time as the echocardiographic measurements.
Clinical predictors
The predictors (covariates) evaluated included patient demographic data such as age, gender, and body surface area; co-existent medical conditions such as hypertension, history of myocardial infarction, congestive heart failure, AF, presence of right coronary artery disease; pre-operative medication use such as antiarrhythmic agents, and beta-bloing agents; surgical factors such as the use of pre-operative intra-aortic balloon counter pulsation, aortic cross-clamp and bypass times, number of grafts, subjective evaluation of myocardial protection by surgeons, atrial activity on surface electrocardiography during cardiopulmonary bypass, and the use of intraoperative defibrillator; and post-operative conditions such as return to the operating room, and perioperative myocardial infarction and heart failure.
Outcome assessment
All patients were followed daily until discharge with continuous electrocardiographic telemetry for the occurrence of post-operative AF. AF was defined as absence of P waves, replaced by irregular fibrillation waves, or no sign of atrial activity lasting for an arbitrary duration of 30 min.22 All telemetry data were downloaded onto a computer and reviewed daily by an investigator not involved in the clinical care of the patient. Two investigators validated all episodes of AF using hard copy printouts. Post-operative myocardial infarction was defined as new Q waves (
40 ms, 25% R-wave) on post-operative 12-lead electrocardiography and CPK-MB isoenzyme concentration
50 U/l.
Statistical analysis
Exploratory data analyses were carried out using univariate summaries to examine distributions of key variables. This initial analysis allowed us to screen the data for potential errors, outliers and influential observations and further identify transformations for variables with skewed distributions if necessary. More detailed analyses were performed using two-sample comparisons such as Wilcoxon rank-sum tests, and two-sided Chi Square tests to identify potential associations, target predictors and confounders for multivariable analysis.
Finally, the association of potential clinical predictors with the occurrence of post-operative AF was evaluated one variable at a time with logistic regression. Variables that had significant association with post-operative AF on univariate analysis (P value⩽0.1) were entered in a multivariable logistic regression model (SAS 8.2). Continuous variables such as age and body surface area were initially stratified into quartiles and each quartile was compared to the lowest quartile. If any variable demonstrated linearity, the variable was treated as continuous for subsequent analyses.
After the model including the clinical predictors was constructed, each Doppler variable significant on univariate analysis was added to the model separately to see if the model improved using the likelihood ratio test. The final full model (including clinical predictors and echocardiographic variables) and the restricted model (with only clinical predictors) were compared using the likelihood ratio test. The fit of the model was assessed using the HosmerLemeshow goodness-of-fit test. The model with the "best fit" and in which all variables retained a P-value<0.05, was chosen as the final model. P-values and odds ratios (OR) with 95% confidence interval are reported. P<0.05 was considered statistically significant. All data were presented as means±standard deviation unless stated otherwise.
Haemodynamic data measured during the pre-bypass and post-bypass periods were analysed by repeated measures ANOVA and group-by-time interaction. Comparison of the pre-bypass and post-bypass echocardiographic data were assessed by the MannWhitney (Wilcoxon) Test.
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Results |
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Discussion |
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The changes in atrial function are reflected by a number of echocardiographic measurements. VTI of the mitral inflow signal is considered to be an analogue of left atrial stroke volume, or conduit function. Patients who developed subsequent post-operative AF had an increase in the VTI E/A fraction, and a decrease in the atrial filling fraction. Alterations in autonomic nervous system activity affects the left atrial inotropic state similar to that occurring in the left ventricle.24 The finding that patients who subsequently developed post-operative AF had an increased left atrial stroke volume suggests that an increased autonomic nervous system activity may have been a link to the pathophysiology of post-operative AF, a phenomenon suggested by a previous study.25 Alternatively, the increase in left atrial conduit function and a decrease in atrial filling fraction may be a marker of increased left atrial afterload, possibly secondary to the increased left ventricular stiffness as evidenced by abnormal relaxation in our results. In an animal model of rapid pacing-induced atrial failure,26 an impaired booster pump and increased conduit function have been observed, similar to our current findings. Mechanism for atrial abnormalities is not known but a possible aetiology may include atrial stunning and/or ischaemia after open-heart surgery. In the present study, the atrial abnormalities occur predominantly after cardiopulmonary bypass, suggesting that surgery and/or cardiopulmonary bypass may have been a "triggering" factor. Although our study demonstrated that the adequacy of myocardial protection, as assessed clinically, was similar between patients with and without post-operative AF, more sensitive techniques may be necessary to demonstrate the adequacy of atrial protection during cardiopulmonary bypass.
Two previous studies in patients undergoing CABG surgery demonstrated conflicting findings, while one demonstrated left atrial appendage area and pulmonary vein velocity to be echocardiographic predictors of post-operative AF,27 the other study showed no differences in transmitral Doppler velocity or left atrial width in patients with and without post-operative AF.28 However, both of these studies are limited by rather small sample sizes. Also, none of these studies assessed the relationship between LA function and post-operative AF.
Although left ventricular systolic performance, as measured by ejection fraction, was similar between patients with and without post-operative AF, abnormal relaxation of the left ventricle is evident in patients who subsequently developed post-operative AF as indicated by the prolonged early mitral inflow and deceleration time of the mitral inflow velocity. In a study of patients >65 years of age referred for echocardiography, Tsang et al.,29 demonstrated that the presence and severity of diastolic dysfunction were independent predictors of AF on long-term follow-up. Abnormal relaxation, in particular, increased the risk of AF independent of the effects of age. It is postulated, although not proven, that abnormal relaxation of the left ventricle may lead to higher atrial pressures during atrial diastole, thereby resulting in an increase in LA volume.30 Over time, the left atrium and pulmonary veins may dilate. Our present results appear to support this hypothesis as patients in our studies were found to have a larger left atrium, left atrial appendage, and pulmonary veins on univariate analysis. Finally, the increase in hepatic vein velocity is suggestive of increase in right atrial pressure, although hepatic vein flow is influenced by multiple factors including atrial relaxation, diastolic flow velocity and ventricular diastolic function.
Aside from the importance of left atrial function and dimension, findings from previous studies in both population and surgical patients agree with our result that advanced age is an independent predictor of AF. Ageing may lead to the loss of myocardial fibres and an increase in fibrosis8,31 causing remodelling of the atrial myocardium. We also found that body surface area to be an independent predictor of post-operative AF, as did a previous report.32 Speculations for this association have included that a large body surface area secondary to increase in adipose tissue may constitute a fertile anatomical substrate for the development of post-operative AF,33 and larger atria and/or differences in intrathoracic pressure may alter the electrophysiological properties of the atrium making them susceptible to atrial arrhythmias after surgery.34 In contrast, our study, along with others,2,35 did not confirm the finding that men have a higher risk of post-operative AF than women.4,36 Gender is likely only a surrogate marker of body size since women generally have a smaller body surface area then men, and body surface area is an independent predictor of post-operative AF in our study.
Our results also demonstrate that Hispanics and possibly Blacks have lower risk of post-operative AF than whites. To date, there are few published studies of post-operative AF in non-White populations. In the Cardiovascular Health Study, a four-community study of elderly subjects, the investigator reported that there was a trend for Blacks to have a lower incidence of AF than Whites (relative risk 0.47, 95% CI 0.221.01).37 Furthermore, Black men were found to have smaller left atrial dimension than white men in multivariable analysis.38 In another study of patients attending an urban hospital, AF occurred in 2.5% of Black patients compared with 7.8% of White patients.39 In the Cardiovascular Health Study, the investigators reported that the race-left atrial dimension relation was diminished after "adjustment for spirometric lung volumes and chest dimensions". We cannot adjust for these measurements in our study as these volumetric measurements were not obtained. As a result, it remains unclear as to the mechanism of how race interacts with post-operative AF.
Potential limitations
Our study only investigated AF which occurred during the in-hospital period. As a result, we may have underestimated the incidence of AF that may have occurred in the late post-operative, out-of-hospital period. For example, the median hospital stay for the group without post-operative AF in our study was 4.5 days, versus 6 days in those with AF. Keeping patients hospitalised for up to one week after surgery may allow us to detect late episodes of AF. However, prolonging the hospitalisation for those without early post-operative complications would likely be financially prohibitive. Second, we used clinically available means to assess the adequacy of atrial protection during cardiopulmonary bypass, such as the presence of atrial activity on surface electrocardiographic monitoring and subjective evaluation of the adequacy of myocardial protection, etc. These measures may not be sensitive enough to detect more subtle atrial changes related to surgery and/or cardiopulmonary bypass. Third, our study did not aim to locate the foci of AF, as our echocardiographic measurements were performed intraoperatively, before the occurrence of subsequent AF. Unlike electrocardiography, it is not feasible to perform continuous echocardiography until the development of AF. Fourth, our measurements of LA function were static, albeit conducted serially, without varying loading conditions. However, comparison of the pre-bypass versus the post-bypass measurements provided information on the impact of surgery on LA function. Finally, we did not measure right atrial function, which may have provided additional information on how changes in biatrial function and dimension relate to post-operative AF.
Clinical implications
Our study demonstrates for the first time that some of the structural and functional changes in the atria common to chronic AF in the elderly population are also prevalent in surgical patients who develop post-operative AF. However, despite the observed changes in atrial function, we were unable to demonstrate any surgical factor that might have led to such atrial changes. Of all the indices of left atrial function and dimension which contributed to an increased risk of post-operative AF, low atrial systolic function and evidence of prolonged diastolic filling measured in the post-bypass period are the most important independent factors associated with increased risk of post-operative AF. These results suggest that atrial dysfunction likely precedes the development of post-operative AF.
Our results suggest that a selective therapeutic approach involving clinical risk prediction (age >70 years, body surface area >2.12 m2, white race, and Doppler findings demonstrating impairment of the atrial systolic function and diastolic filling) should be investigated as a possible strategy of prophylaxis in patients undergoing cardiac surgery. Potential therapies worthy of consideration not only include antiarrhythmic agents, but also strategies to decrease left atrial size and improvement of left ventricular diastolic filling. In addition, investigations of how atrial function varies with loading conditions may shed light on the mechanism of atrial dysfunction preceding the onset of post-operative AF.
Finally, determining whether these structural and functional changes in the atria detected intraoperatively are prognostically important in influencing future chronic AF will be important. These long-term outcome studies may provide further evidence for the possible common pathophysiology between post-operative and chronic AF, ultimately leading to useful therapy in the larger elderly cohort afflicted with chronic AF.
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Acknowledgments |
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References |
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