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Ann Thorac Surg 2006;82:97-102
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

C-Reactive Protein Levels and Atrial Fibrillation After Cardiac Surgery in Women

^a Department of Anesthesiology, St. Louis, Missouri
^b Division of Cardiothoracic Surgery, Department of Surgery, St. Louis, Missouri
^c Department of Neurology, St. Louis, Missouri
^d Cardiovascular Division, Department of Medicine, and the Washington University School of Medicine, St. Louis, Missouri

Accepted for publication February 22, 2006.

^_* Address correspondence to Dr Hogue, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Tower 711, 600 N Wolfe St, Baltimore, MD 21287-8711 (Email: chogue2{at}jhmi.edu).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Notice From the American... Acknowledgments References

 
BACKGROUND: The aim of this study was to evaluate whether risk for postoperative atrial fibrillation in women is related to preexisting inflammation as detected by plasma C-reactive protein (CRP) concentrations. We further sought to assess the importance of atrial fibrillation for outcome after cardiac surgery in women.

METHODS: The CRP was measured before coronary artery bypass grafting and (or) valvular surgery using cardiopulmonary bypass in 141 women. Univariate and multivariate analyses were used to evaluate for differences in CRP levels between women with and without atrial fibrillation, and to assess for the importance of the arrhythmia and postoperative outcomes.

RESULTS: Atrial fibrillation developed in 46 (33%) women. Neither CRP concentrations (median ± standard error, 13.3 ± 2.5 mg/L vs 11.7 ± 1.4 mg/L, p = 0.847), nor the frequency of elevated levels (defined as > upper 95% confidence interval or >19.2 mg/L) (19% vs 21%, p = 0.807) differed between women with or without atrial fibrillation. Patient age and previous stroke, but not CRP levels, were independently associated with atrial fibrillation. Women with atrial fibrillation were more likely to have low cardiac output syndrome (p = 0.018), stroke (p = 0.031), longer duration of hospitalization in the intensive care unit (p = 0.012) and on the postoperative (p = 0.0008) ward, and they were more likely to require an extended care facility after surgery (p = 0.046).

CONCLUSIONS: In contrast to findings from studies that have included mostly men, preoperative CRP concentrations are not associated with risk for atrial fibrillation after cardiac surgery for women. Postoperative atrial fibrillation in women is associated with increased risk for stroke, longer hospitalization, and extended care facility admission.

	Introduction

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Women represent a minority of patients undergoing cardiac surgery yet they have been consistently shown to have higher morbidity and mortality than men [1–4]. In several studies our group has found that higher operative mortality in women can be explained in part by perioperative stroke [2–4]. Risk for stroke in these single-center and multicenter studies could not be explained by known stroke risk factors. Atrial fibrillation is a common complication after cardiac surgery and a potentially preventable cause of stroke and other adverse events [5–7]. The arrhythmia is believed to result from multiple cardiac perturbations occurring during surgery in the setting of a preexisting arrhythmogenic substrate [5, 8]. Clinical and histologic investigations suggest that inflammation may play a role in the initiation and (or) maintenance of atrial fibrillation, and that antiinflammatory agents might reduce its frequency [7, 9, 10]. Delineating the role of inflammation in postoperative atrial fibrillation may thus have both mechanistic and therapeutic implications. Identifying susceptibility before surgery might further provide a means for appropriate targeting of both arrhythmia and stroke preventative medications.

C-reactive protein (CRP) is an acute phase reactant produced in the liver in response to inflammatory cytokines, especially interleukin-6 [11]. Extensive data have shown that CRP levels provide independent prediction of adverse cardiovascular events such as myocardial infarction and stroke [11–15]. The role of CRP concentrations in identifying risk for complications after cardiac surgery is increasingly under investigation [16, 17]. A link between CRP levels and atrial fibrillation supports the notion that inflammation enhances susceptibility to the arrhythmias regardless of whether the surgery is performed with our without cardiopulmonary bypass [18–22]. Patient sex can influence multiple physiologic processes including inflammation and CRP levels [23]. Prior investigations that have evaluated inflammatory mechanisms of atrial fibrillation, though, have included mostly men, limiting extrapolation of the findings to women.

The hypothesis of this study is that CRP concentrations measured before surgery are elevated in women who develop atrial fibrillation after cardiac surgery compared with women remaining in sinus rhythm. Because most studies that have investigated postoperative atrial fibrillation have not provided separate analysis based on patient sex, we further sought to assess for the importance of atrial fibrillation and other adverse outcomes after cardiac surgery for women.

	Patients and Methods

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Study Patients and Investigative Protocol
All procedures of this study met with the approval of the Human Studies Committee of Washington University School of Medicine, St Louis, Missouri on May 12, 1999 and were performed only after receiving individual informed consent. Participants were part of a prospectively randomized double-blind outcome study of perioperative 17ß-estradiol replacement for postmenopausal women undergoing cardiac surgery. Data for the current report were made available after the first planned interim analysis of that trial. Women greater than 55 years of age, or those younger with prior oophorectomy, scheduled for elective coronary artery bypass graft (CABG) surgery and (or) cardiac valvular surgery were eligible. Exclusion criteria included the following: (1) surgery not using cardiopulmonary bypass; (2) elevation of liver function tests before surgery or creatinine before surgery (>2 mg/dL); (3) emergency surgery; (4) severe cognitive impairment before surgery as indicated by clinical history and (or) a score greater than 12 on the Short Blessed Dementia Screening Test; (5) inability to attend outpatient visits; (6) history of venous thromboembolism; (7) unexplained vaginal bleeding; (8) history of breast cancer or personal history of endometrial cancer in the absence of hysterectomy; (9) estrogen use within 6 months of the surgery; (10) inability to speak and read English or visual impairment.

Perioperative Care
Patients received an opioid-based anesthetic supplemented with muscle relaxants and volatile anesthetics aimed at early tracheal extubation. After heparin administration, nonpulsatile cardiopulmonary bypass was instituted using a membrane oxygenator and a 40 µm arterial line filter in the circuit. Blood flow was between 2.0 and 2.4 L^–1 · min^–1 · m^–2 and urinary bladder temperature ranged between 32°C and 34°C. Alpha-stat pH management was used. Mean arterial blood pressure during cardiopulmonary bypass was maintained between 50 mm Hg and 80 mm Hg with phenylephrine, sodium nitroprusside, or by altering the concentration of volatile anesthetic delivered to the cardiopulmonary bypass circuit. Blood glucose was measured at the onset of cardiopulmonary bypass and every 30 minutes, and regular Humulin insulin (Eli Lilly, Indianapolis, IN) given when glucose was greater than 200 mg/dL. Pericardial aspirate was returned to the cardiopulmonary bypass circuit. A protamine dose given at the conclusion of cardiopulmonary bypass was calculated using the heparin-protamine titration method (Hepcon, Medtronics, Minneapolis, MN) as previously described [24].

The patients were evaluated daily after surgery for perioperative complications by a member of the investigative team. All patients had continuous electrocardiographic (ECG) monitoring, using a bedside monitor in the intensive care unit and telemetry on the hospital ward until hospital discharge. A 12-lead ECG was obtained before surgery and on the first 4 postoperative days. Troponin I concentrations were measured the day before surgery, immediately after surgery in the intensive care unit, and on the first 4 postoperative days.

C-Reactive Protein Measurement
Venous blood specimens were obtained the day before surgery prior to administration of 17ß-estradiol. The specimens were immediately placed in glass tubes devoid of anticoagulants or preservatives. Serum was separated by centrifugation, placed in plastic tubes, and frozen at –70°C until the time of analysis. The CRP concentrations were measured using a high sensitivity immunonephelometry technique (Dade Behring, Newark, DE). The lower detection limit of the assay is 0.175 mg/L.

Clinical Endpoints
Atrial fibrillation was diagnosed when there was an irregularly irregular cardiac rhythm without P-waves lasting greater than one minute regardless of treatment. This diagnosis was made by the physicians caring for the patients. Twelve-lead ECGs and troponin I data were independently reviewed by two physicians blinded to treatment study assignment. Diagnosis of a Q-wave myocardial infarction was made when there was a new Q-wave greater than 1/3 the height of the ECG R-wave on the 12 lead ECG and a rise in troponin I concentrations greater than 6 ng/mL from the preoperative levels. A non-Q- wave myocardial infarction was diagnosed in the absence of a new Q-wave when there was an increase in the troponin I concentrations greater than 13 ng/mL from the preoperative baseline [25]. A diagnosis of myocardial infarction was by consensus. A third cardiologist was consulted when there was disagreement. Low cardiac output syndrome was defined as a cardiac index less than 2.0 L^–1 · min^–1 · m^–2 for greater than 8 hours regardless of treatment.

Two neurologists blinded to assigned study treatment independently reviewed all cases of clinically diagnosed stroke. Brain imaging results were reviewed when available. The diagnosis of stroke was when there was a new focal or global neurologic deficit that persisted greater than one day and that was not explained by metabolic or pharmacologic causes.

Statistical Analysis
Data analysis was performed with a personal computer using Stata Software (Stata Corp, College Station, TX). Dichotomous data were analyzed with ² testing and continuous data with one-way analysis of variance. Demographics, clinical information, and CRP concentrations were compared between patients with and without postoperative atrial fibrillation. Patients were further categorized as having elevated CRP concentrations when the levels were higher than the 95% confidence interval for the entire patient population. Step-wise multivariate logistic regression analysis was performed to assess for any relation between CRP levels and atrial fibrillation after adjusting for other variables with a p less than 0.2 on univariate analysis.

	Results

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Atrial fibrillation developed after surgery in 46 (33%) of 141 women. Demographic and medical data are listed in Table 1. There were no differences in the variables evaluated between women who developed atrial fibrillation compared with those who remained in sinus rhythm. The frequency of atrial fibrillation was not different for the patients receiving perioperative 17ß-estradiol replacement compared with placebo.

	Comment

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A mechanistic role of inflammation in the pathogenesis of atrial fibrillation was suggested by the findings of inflammatory cell infiltrates in atrial biopsy specimens from affected patients and the known association between the arrhythmia and pericarditis [9, 10]. This speculation was furthered by Bruins and colleagues [18], who reported that CRP-mediated complement activation products (C 4b/c) on the second day after CABG surgery were related to the development of supraventricular arrhythmias (p = 0.0065). Experimentally, electrophysiologic changes conducive to the development of postoperative atrial fibrillation correlate with degree of inflammation measured by tissue myeloperoxidase activity [27]. Treatment with methylprednisolone reduces both atrial myeloperoxidase activity and the electrophysiologic substrate for atrial fibrillation. Elevated CRP might be directly involved in the genesis of atrial arrhythmias by binding to phosphocholine moieties on cell membranes altering cellular calcium handling, or it may merely serve as a marker for other inflammatory processes more directly related to the development of atrial fibrillation [11, 28–31].

Several investigations have shown a relation between CRP and atrial fibrillation in surgical and nonsurgical populations. Chung and colleagues [(19] found that CRP concentrations were twofold higher in 131 nonsurgical patients with atrial fibrillation compared with 71 individuals in sinus rhythm (p < 0.001). These results were confirmed in an analysis of data from the Cardiovascular Health Study, a population-based study involving 5,806 individuals [20]. In that study, CRP levels predicted baseline and future risk for atrial fibrillation after nearly 7 years of follow-up. Gaudino and colleagues [16] reported that patients with the –174 G/C interleukin-6 promoter genotype had more marked elevations in inflammatory cytokines after CABG surgery using cardiopulmonary bypass and that this accentuated inflammatory response was associated with postoperative atrial fibrillation. More recently Lo and colleagues [22] found a relation between preoperative CRP levels and atrial fibrillation after CABG surgery. For those undergoing surgery on-pump, postoperative atrial fibrillation developed in 55% of patients with high baseline CRP (>3.0 mg/L,) but in only 21% of patients with low baseline CRP (p = 0.01). Atrial fibrillation developed after off-pump surgery in 8% of patients with low baseline CRP and in 30% with high baseline CRP (p = 0.002). In that study CRP remained an independent predictor of atrial fibrillation even after adjusting for other risk factors with multivariate logistic regression analysis.

Studies reporting a relation between elevated CRP and atrial fibrillation susceptibility have included mostly men. The need to report, separately, clinical trial data for men and women is increasingly recognized because patient sex can modify many pathophysiologic processes including inflammation [23, 32, 33]. Based on population-based assessments, the Center for Disease Control and the American Heart Association guidelines suggest that a CRP level of greater than 3 mg/L represents a high risk for vascular disease [26]. Other data, however, suggest that women have higher baseline CRP levels than men. In the Dallas Heart Study, for example, median CRP levels were higher for women compared with men (3.3 mg/L vs 1.8 mg/L, p < 0.001) [23]. Fifty-one percent of white women and 58% of black women had levels greater than 3.0 mg/L compared with only 31% and 40% of white and black men, respectively (p < 0.001). In the current study, 76% of women with and 73% of women without atrial fibrillation had CRP concentrations greater than 3 mg/L.

Conceivably, the higher level of inflammatory response to acute cardiovascular disease in women overwhelms the ability to distinguish a true baseline level of inflammation as might be related to risk for atrial fibrillation. Alternatively, inflammatory processes may play a bigger role for determining atrial fibrillation susceptibility for men than women. It is also feasible that the mechanisms of postoperative atrial fibrillation may differ between women and men. Women undergoing cardiac surgery more often than men have preserved left ventricular function, yet more frequently have hypertension and congestive heart failure [1–4]. These findings would be expected to lead to left ventricular diastolic dysfunction that might promote higher atrial pressures and atrial distention. The latter could activate atrial stretch receptors promoting electrophysiologic conditions for atrial fibrillation [34, 35]. We are unable to assess these potential mechanisms for atrial fibrillation for women in this small cohort.

In this study we report only CRP concentrations before surgery. Our intent was to evaluate for evidence of preexisting inflammation as a means to identify individuals with the substrate for atrial fibrillation before surgery. Measurements in the postoperative period may have identified a link between inflammation and atrial fibrillation. Others have shown, though, that the concentrations of this inflammatory marker peak on postoperative days 3 to 4, a time frame similar to the onset of atrial fibrillation [16–18]. To avoid the confounding influence of inflammation resulting from atrial fibrillation and (or) its treatments, postoperative specimens would have to be collected before the onset of the arrhythmia. Not only would this be difficult to ensure clinically, but these specimens would likely be obtained prior to peak CRP levels are achieved. Baseline CRP concentrations have been found to be the strongest predictor of postoperative levels suggesting that "high" responders to the well-described inflammatory effects of cardiac surgery with cardiopulmonary bypass would be identified by measurements before surgery [16–18, 36].

Multiple investigations have reported the frequency and importance of atrial fibrillation for patient outcomes after cardiac surgery [5, 7, 8]. These reports have not evaluated separately whether this relationship specifically applies to women, who represent a minority of the studied patients. Our findings, though, are similar to the reports composed mostly of men. In this study, women developing atrial fibrillation were more likely than those remaining in sinus rhythm to have other cardiac and neurologic complications. We did not determine the temporal relationship between the onset of atrial fibrillation and these complications [7]. Thus, we cannot distinguish whether these associations were causally related or secondarily related to these events (ie, stroke or low cardiac output occurred because of atrial fibrillation or vice versa). Our findings that women with atrial fibrillation were hospitalized nearly 3 days longer than those without atrial fibrillation, and that they were nearly twice as likely to be discharged from the hospital to an extended care facility, are consistent with prior reports. Although the limitations of the small sample size of this study must be acknowledged, our data appear to confirm that the association between atrial fibrillation after cardiac surgery and other complications and health resource utilization applies to women.

	Notice From the American Board of Thoracic Surgery

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The 2006 Part I (written) examination will be held on Monday, December 4, 2006. It is planned that the examination will be given at multiple sites throughout the United States using an electronic format. The closing date for registration is August 1, 2006. Those wishing to be considered for examination must apply online at www.abts.org.

To be admissible to the Part II (oral) examination, a candidate must have successfully completed the Part I (written) examination.

A candidate applying for admission to the certifying examination must fulfill all the requirements of the Board in force at the time the application is received.

Please address all communications to the American Board of Thoracic Surgery, 6333 N St. Clair St, Suite 2320, Chicago, IL 60611; telephone: (312) 202-5900; fax: (312) 202-5960; e-mail: mailto:info{at}abts.org.

	Acknowledgments

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This study was supported in part by a grant from the National Institutes of Health (RO1 HL64600, Dr Hogue principle investigator).

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jennifer S. Lawton Ralph Damiano Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hogue, C. W. Articles by Damiano, R. Search for Related Content PubMed PubMed Citation Articles by Hogue, C. W., Jr Articles by Damiano, R. Related Collections Electrophysiology - arrhythmias