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Pace_00568.tex

Autonomic Control in Patients Experiencing Atrial
Fibrillation After Cardiac Surgery
ROBERT BAUERNSCHMITT, M.D.,* HAGEN MALBERG, PH.D.,† NIELS WESSEL, PH.D.,‡
GERNOT BROCKMANN, M.D.,* STEPHEN M. WILDHIRT, M.D.,* BURKHARD KOPP, PH.D.,*
J ¨
URGEN KURTHS, PH.D.,‡ GEORG BRETTHAUER, PH.D.,† and R ¨ From the *Department of Cardiovascular Surgery, German Heart Center, Munich, Germany, †Institute for AppliedComputer Science, Forschungszentrum Karlsruhe (Karlsruhe Research Center), and ‡Department of Physics,University of Potsdam, Germany Background: Atrial fibrillation (AF) occurs in 20–40% of patients after open heart surgery and leads
to an increased morbidity and prolonged hospital stay. Earlier studies have demonstrated that depressedbaroreflex function predicts mortality and major arrhythmic events in patients surviving myocardial in-farction. Cardiac surgery per se leads to decreased baroreflex sensitivity (BRS) and heart rate variability(HRV). Hence, the present study was aimed at analyzing the impact of the cardiovascular autonomoussystem on the development of postsurgical AF. Methods and Results: The study covered 51 patients who consecutively underwent aortic valve replace-
ment, coronary artery bypass surgery, or combined procedures. Noninvasive blood pressure and ECG wererecorded the day before and 24 hour after surgery. BRS, linear as well as nonlinear HRV parameters werecalculated using established methods. Eighteen patients developed AF during the first postoperative week,while 33 remained in sinus rhythm (SR) throughout the observation period. Patients with postoperative(PostOp) AF exhibited a significantly reduced preoperative (PreOp) BRS in terms of bradycardic andtachycardic regulation (average delayed slope [ms/mmHg]: SR: PreOp: 9.83 ± 3.26, PostOp: 6.02 ± 2.29,Pre-Post: P < 0.001; AF: PreOp: 7.59 ± 1.99, PostOp: 6.39 ± 3.67, Pre-Post: P < 0.044; AF vs SR: PreOp:P < 0.01, PostOp: ns). In both groups, surgery caused a decrease of BRS and HRV. Analysis of nonlineardynamics revealed a tendency toward decreased system complexity caused by the operation; this trendwas significant in patients remaining in sinus rhythm. Conclusions: Patients experiencing postoperative AF obviously suffer from an impaired BRS before
surgery already. These findings may be used to guide prophylactic antiarrhythmic therapy. (PACE 2007;30: 77–84) atrial fibrillation, cardiac surgery, heart rate variability, baroreceptor sensitivity, antiarrhythmic
therapy

Introduction
atrial morphology, and preexisting electrocardio- Supraventricular arrhythmias occur with an gram (ECG) abnormalities, but also the intraoper- abundance of 20–40% after open heart surgery de- ative stress, including reperfusion, inflammation, spite improvements in anesthesia, surgical tech- hemostasis, and increased excitotoxicity, plays a nique, and medical therapy.1 The most common role.3,4 However, the precise contribution of each types of arrhythmias are atrial fibrillation (AF) or risk factor, the pathophysiological mechanisms, atrial flutter. While postoperative arrhythmias are and the role of the cardiovascular autonomous sys- seldom life-threatening, they can increase morbid- tem in the postoperative patient are still widely ity and the duration of hospitalization with in- creased health care costs.2 The pathogenesis of It is well known from earlier studies that the postoperative AF is considered to be multifacto- state of the autonomous tone has a major impact on rial. One factor is the patient’s preoperative status, survival and the occurrence of arrhythmias in pa- such as age, reduced left ventricular (LV) function, tients after myocardial infarction8,9 and is severelyaltered in patients with dilated cardiomyopathy.10Based on these findings, it was demonstrated in apilot study11 that a severe imbalance of the vagal This study was supported by grants from the Deutsche and sympathetic response can be observed imme- Forschungsgemeinschaft (DFG BA 1581/4-1, BR 1303/8-1, KU diately after an open heart surgery with extracor- poreal circulation. It might indicate an increased Address for reprints: Robert Bauernschmitt, M.D., Depart- susceptibility to arrhythmic events. The aim of ment of Cardiovascular Surgery, German Heart Center Mu-nich, Lazarettstr. 36, Munich, 80636, Germany. Fax: +49-89- the study presented here was to analyze the in- 12184093; e-mail: [email protected] fluence of pre- and postoperative cardiovascularautonomous control on the occurrence of postop- Received February 25, 2006; revised September 7, 2006; ac-cepted October 6, 2006.
C 2007, The Authors. Journal compilation C 2007, Blackwell Publishing, Inc.
Patients and Methods
sis. One week after surgery, the patients were di- Fifty-eight patients consecutively undergoing vided into two groups: patients remaining in sinus isolated aortocoronary bypass surgery, isolated rhythm (group SR, n = 33) and patients experienc- aortic valve surgery, or combined aortic valve re- ing at least one episode of AF lasting longer than placement and bypass surgery were included in 5 minutes (group AF, n = 18). Demographic and the study after approval of the local committee operative data are given in Table I.
of ethics and informed consent. Exclusion crite- After 10-minute equilibrations to the environ- ria were emergency operations, a history of AF or ment, noninvasive blood pressure signals were ventricular arrhythmias, and the use of the radial collected from the radial artery by a tonometer artery as bypass graft, because the contralateral ra- (Colin Medical Instruments, San Antonio, TX) at dial artery was used for invasive pressure monitor- 1,000 Hz. Data were channeled into a bed-side laptop after A/D conversion and stored for anal- ysis. Simultaneously, breathing excursions and a formed in a standardized manner with sufentanil standard ECG were monitored. Data were sampled and midazolam. For maintaining narcosis, a con- for a 30-minute period the day before surgery at tinuous infusion of propofol was given; muscle re- the hemodynamic laboratory and 24 hours after laxation was achieved by pancuronium. Central surgery on the ICU. Care was taken to perform the venous pressure and pulmonary artery pressure measurements during the same time of the day for were monitored by a Swan-Ganz catheter, arterial each patient. From the data recorded, the beat- pressure by cannulation of the radial artery. All op- to-beat intervals as well as the beat-to-beat sys- erations were carried out with a cardiopulmonary tolic and diastolic values were extracted; prema- bypass (CPB) in a mild hypothermia (32◦C–34◦C) ture beats, artifacts, and noise were excluded using and pulsatile perfusion mode; cold crystalloid an adaptive filter considering the instantaneous cardioplegia or blood cardioplegia (isolated by- pass surgery) was used for cardiac arrest. After For statistical analysis, the Mann-Whithey U declamping, most of the patients needed one coun- test was applied to find differences of the calcu- tershock to terminate ventricular fibrillation.
lated parameters. To check for the equality of pro- The occurrence of atrial fibrillation or of a portions and independence, the χ2 test was ap- severe psychosyndrome (first postoperative day), mechanical ventilation (>20 hours after surgery),and the need for inotropic support (>low-dose Analyses
dopamine 24 hours after surgery) led to post hoc Baroreflex Sensitivity (BRS): Dual Sequence
exclusion; thus, 51 patients remained for analy- Method (DSM)
Using the DSM, the parameters most relevant to estimating the spontaneous baroreflex (BR) are the coupling slopes of RR intervals (RRI) and sys-tolic blood pressure (SBP) as a measure of sensi- standard sequence methods with several modifi- PostOp SR PostOp AF P-value
cations.13 Two kinds of RRI responses were ana-lyzed: bradycardic (an increase in SBP that causes an increase in the following RRI) and tachycardic fluctuations (a decrease in SBP causes a decrease in RRI). Both types of fluctuations were analyzed in a synchronous and in a 3-interbeat-shifted mode.
The bradycardic fluctuations primarily reflect the vagal spontaneous BR.14,15 Tachycardic fluctua- tions reflect the delayed responses of the heart rate (shift 3) that result from the beginning slower sym- The following parameter groups are calcu- lated by DSM: (1) the total numbers of slopes in PostOp SR = postoperative sinus rhythm; PostOp AF = different sectors within 30 minutes; (2) the per- postoperative atrial fibrillation; ECC = extracorporeal circulation; centage of the slopes in relation to the total number LVEF = left ventricular ejection fraction; NYHA = New York of slopes in the different sectors; (3) the numbers Heart Association class; ns = not significant.
*Application of β-blockers was continued immediately after of bradycardic and tachycardic slopes; (4) the shift operation from the first (sync mode) to the third temporal changes in the autonomic tonus.19,20 Sev- eral new measures of nonlinear dynamics as pro- posed by Wessel et al.,12 Kurths et al.,21 and Voss et al.22 were used. The concept of symbolic dy-namics is based on a coarse-graining of dynamics.
The difference between the current value (RRI or SBP) and the mean value of the whole series is transformed into an alphabet of four symbols (0;1; 2; 3). Symbols “0” and “2” reflect small devi-ation (decrease or increase) from the mean value, whereas “1” and “3” reflect a larger deviation (de-crease or increase beyond a predefined limit, for details see Voss et al.22 Subsequently, the symbol SBP [mmHg]
string is transformed to “words” of three succes-sive symbols explaining the nonlinear properties Figure 1. Schematic representation of the two main
and, thus, the complexity of the system. The Renyi baroreflex parameters estimated by the Dual Sequence entropy calculated from the distributions of words Method: the average slope (dotted line) of all barore- (“fwrenyi025” – a = 0.25) is a suitable measure flex sequences as well as the total number of baroreflex of the complexity in the time series (“a” repre- slopes above 20 ms/mmHg (thick lines). The thin lines sents a threshold parameter). Higher values of en- symbolize all baroreflex slopes below 20 ms/mmHg. tropy refer to higher complexity in the correspond-ing time series and lower values to lower ones. Ahigh percentage of words consisting of the symbols (shift 3 mode) heartbeat triple; and (5) the average “0” and “2” only (”wpsum02”) reflect a decreased slopes of all fluctuations. DSM parameters are de- HRV. The parameter “Forbidden words (FW)” re- fined as described by Malberg et al.17 Figure 1 rep- flects the number of words that never or very rarely resents a scheme of the two main DSM parameters occur. A high number of forbidden words is typ- used in this study: the average baroreflex slope as ical of a regular behavior, while very few forbid- well as the total number of baroreflex slopes above den words only are found in highly complex time series. When introducing an additional parame-ter as suggested by Wessel et al.23,24 six successive Heart Rate (HRV)
symbols of a simplified alphabet, consisting of the In line with the suggestions made by the Task symbols “0” or “1” only, were observed. Here, the Force HRV,18 the following standard parameters symbol “0” represents a difference between two are calculated from the time series: MeanNN (mean successive beats lower than a certain limit (10 ms value of normal beat-to-beat intervals): this pa- in our study), whereas “1” represents cases with rameter is inversely related to the mean heart a difference between two successive beats exceed- rate. SdNN (standard deviation of intervals be- ing this limit: Words consisting of the unique type tween two normal R-peaks): it gives an impression of symbol “0” only were counted. The parameter of the overall circulatory variability. Rmssd (root “polvar10” depicts the probability of occurrence mean square of successive RR-intervals): higher of the word type “000000” with the limit of 10 ms values indicate higher vagal activity. Shannon (the and detects an intermittently decreased HRV.
Shannon entropy of the histogram): quantificationof RR-interval distribution. Apart from the time- domain parameters mentioned above, the HRV Figures 2 and 3 exemplarily show the tracings analysis focused on high-frequency components of systolic and diastolic pressure (first panel) as (HF, 0.15–0.4 Hz, high values indicate vagal activ- well as of the RR-intervals (second). Figure 2 rep- ity) and low-frequency components (LF, 0.04–0.15 resents the preoperative measurements, while the Hz, high values indicate sympathetic activity).
curves in Figure 3 have been recorded postopera- The following ratios were considered: LFn—the tively. Pure visual inspection gives the impression normalized low frequency (LFn = LF/(LF+HF)), of an overall reduced variability after the surgical HP/P—high frequency normalized to the total power P as well as LP/P—the P-normalized lowfrequency.
Clinical Course
New parameters can be derived from methods All patients included in the study survived the of nonlinear dynamics, which describe complex operation and did not suffer from major adverse processes and their interrelations. These methods events in the immediate postoperative course.
provide additional information about the state of Eighteen of the 51 patients developed at least one Figure 4. Baroreflex sensitivity. Average slope of the
bradycardic synchronous baroreflex in the range of 3– 30 ms/mmHg. Black bars: group SR, white bars: group AF. ***P < 0.001 versus preoperative; P < 0.01 versusgroup SR. Figure 2. Tachograms of blood pressure and heart rate
in one patient (example), which were recorded preoper-
atively, first panel: systolic and diastolic blood pressure,

patients in the AF group had a decreased preop-erative bradycardic and tachycardic regulation ascompared to patients remaining in sinus rhythm.
episode of AF lasting longer than 5 minutes within Postoperatively, there were no differences between Baroreflex Sensitivity
Heart Rate Variability
In patients with a postoperative sinus rhythm, The HRV parameters obtained are presented the strength of bradycardic and tachycardic regu- in Table III. Time-domain intragroup comparison lation (average slope) decreased significantly after revealed a significant drop of variability parame- surgery. Patients experiencing postoperative AF ters due to the surgical intervention in both groups.
showed a significant preoperative decrease in BRS No differences of time-domain parameters were compared to patients remaining in SR (Fig. 4).
noticed between groups, neither pre- nor postoper-atively. The parameter “Shannon” showed a uni-form decrease in both groups (Fig. 5).
ters, both groups exhibited a similar behavior. Themost obvious difference between pre- and post- operative measurements was a decrease of power in all frequency ranges, which was caused by theoperation. Patients experiencing postoperative AF had a tendency to show a reduced power in all ranges before the operation compared to patients remaining in sinus rhythm (SR). Due to the rela- tively high standard deviations, however, statisti- cal significance was reached for LF/P only.
The nonlinear parameter “Forbidden Words” FW showed a significant increase in patients re-maining in sinus rhythm after surgery. In patients with a postoperative AF the trend was not signif- icant. Preoperatively, the AF group had a higher number of forbidden words than the SR group;postoperative analyses did not reveal any inter- Figure 3. Tachograms of blood pressure and heart rate
in the same patient (Fig. 2), but recorded postopera- Regarding the symbolic dynamics, there was tively, first panel: systolic and diastolic blood pressure, a clear and significant trend toward a decreased system complexity after surgery in patients Table II.
Baroreflex Sensitivity Calculated by the Dual Sequence Method SR versus AF
Pre-Post
Pre-Post PreOp PostOp
Parameter
P-value P-value P-value
6.02 ± 2.29 <0.001 7.59 ± 1.99 6.11 ± 3.13 <0.001 7.48 ± 1.25 9.65 ± 10.42 1.81 ± 6.30 <0.001 2.96 ± 3.55 6.57 ± 2.64 <0.001 7.82 ± 1.97 9.99 ± 12.52 3.61 ± 7.59 <0.001 4.76 ± 5.27 7.34 ± 2.64 <0.001 8.09 ± 1.86 PostOp SR = postoperative sinus rhythm; PostOp AF = post-operative atrial fibrillation; Dual sequence method parameters; brady˙sync = synchronous bradycardic slope of the heart rate following an increase in systolic blood pressure; tachy˙shift = delayed (3 beats)tachycardic slope of the heart rate following a decrease in systolic blood pressure (brady˙shift, tachy˙sync resp.); av. Slope = averageslope [ms/mmHg]; Slopes sect = number of high BR (range >20 ms/mmHg in [%]) related to the total number of BR events; ns = notsignificant.
maintaining sinus rhythm. In patients with post- between the groups was observed for the param- operative AF, only a few parameters showed sig- eters “Forbidden Words” and Fwrenyi025 only.
nificant pre- and postoperative differences. While Hence, the difference between the groups cannot most parameters indicated a trend toward a de- be expressed by the pre- or postoperative measure- creased complexity in AF patients as compared to ment data per se, but by the dynamics from the pre- SR patients, a significant preoperative difference Table III.
Heart Rate Variability, Selected Time and Frequency Domain as well as Nonlinear Parameters SR versus AF
Pre-Post
Pre-Post
869.5 ± 134.1 732.2 ± 87.2 P < 0.001 904.0 ± 127.9 747.6 ± 129.9 P < 0.001 PostOp SR = postoperative sinus rhythm; PostOp AF = postoperative atrial fibrillation, time-domain parameters; meanNN = mean valueof a normal-to-normal beat interval; sdNN = standard deviation of the normal-to-normal (NN) intervals; rmssd = root mean square ofsuccessive NN-interval differences; frequency domain parameters: LFn, HF/P, LF/P for definition of frequency bands see methodssection; nonlinear parameters; FW = forbidden words; FWRreny025i = Renyi distribution of forbidden words; Wpsum02 = percentage ofwords consisting of the symbols “0” and “2” only; polvar10 = probability of the word type “000000” derived from symbolic dynamicswithin the special limit of 10 ms; ns = not significant.
Baroreflex Sensitivity
In the preoperative DSM analysis, a signifi- cantly lower BRS for the bradycardic and tachy-cardic regulation was found in patients, who laterdeveloped postoperative AF. At first sight, thesefindings seem to sharply contrast with an earlierwork published by Chen et al.25 where the BRSwas found to be increased in patients with AF.
However, Chen’s study covered patients withoutsurgery and paroxysmal AF. Hence, the discrep-ancies may just reflect the different pathophys-iological mechanisms leading to spontaneous or Figure 5. Shannon entropy. Black bars: group SR, white
postsurgical AF. Herweg and coworkers26 even bars: group AF. **P < 0.01 versus preoperative. ***P < demonstrated that AF can be preceded by either an increase or decrease of the HF component ofthe power spectrum, indicating that vagal stim- Discussion
ulation or depression can cause paroxysmal AF.
These data confirm the assumption that the prob- The analysis of BRS and HRV provides infor- lem of induction of different types of AF in differ- mation about the individual risk in cardiac pa- ent patients is far from being solved. Our results tients and is significantly altered in these patients are partly in agreement with data from patients as compared to healthy volunteers.9,11 In contrast suffering from recurrent AF after cardioversion27 to several previous studies, a more complex and or from a recurrence of ventricular arrhythmias,28 multiparametric approach, including bradycardic thus demonstrating a decreased BRS as a predic- and tachycardic fluctuations of BRS, time and fre- tor of the onset of recurring arrhythmias. Patients quency domain analysis of HRV, and nonlinear dy- remaining in SR showed a significant decrease of namics of HRV, were used. The combination of the strength of regulation in the bradycardic re- these parameters proved to more effectively char- sponses, thus closely matching the results of our acterize the functional state of the cardiovascular pilot study. In patients developing postoperative autonomic system in earlier works.16,17 AF is the AF, this reduction was not significant. The inter- most frequent complication after cardiac surgery group differences were no longer evident 24 hours and potentially leads to subsequent adverse events after surgery. This indicates that the occurrence of like a stroke and to a prolonged hospital stay.2 Nu- postsurgical AF is not solely an effect of surgery, merous attempts have been made to predict this but also due to a certain predisposition that ex- complication from demographic data, ECG abnor- ists prior to surgery already. From these data, it malities, or the atrial size.3–7 Less attention has can be hypothesized that a higher ability of the au- been given to the autonomous control of the car- tonomous nervous system to react to pressure fluc- tuations may be protective to overcome the strong It was shown in a previous study that heart arrhythmic stimuli that are obviously generated by surgery with ECC leads to a marked alteration of the BRS and HRV, as expressed by time andfrequency domain parameters and nonlinear dy-namics, respectively.11 This study only covered Heart Rate Variability
patients with isolated CABG surgery, normal LV After the operation, the time and frequency function, and a mean age of 60 years. As expected, domain parameters of HRV showed a strong ten- the rate of AF and other postoperative complica- dency toward less variability and a predominance tions was low. Consequently, no correlation anal- of sympathetic regulation. There were no major ysis of the autonomous function and clinical pa- differences between the two groups, which is in agreement with previous findings by other authors.
The present study was designed to analyze A reduction of HRV during surgery has already the impact of the cardiovascular autonomous reg- been observed by Souza Neto and coworkers29 and ulation on the occurrence of postoperative AF.
was attributed to the influences of anesthesia. The One third of the patients experienced postopera- postoperative analyses in our patients, however, tive AF, which was within the expected range. The were done several hours after the application of “classical” demographic and operative parameters sedative agents. Hence, a persisting effect of anes- putting patients at a higher risk for postoperative thesia is unlikely. These long-term effects that ob- AF were not different between the two groups (see viously last for months30 are probably caused by a direct damage of neural fibers during surgery.31 In nonlinear dynamics, intragroup compari- could be detected. From these findings, the follow- son between the pre- and postoperative measure- ing conclusions can be drawn: the onset of postop- ments showed a highly significant trend toward a erative AF is not only caused by commonly known reduced system complexity in patients remaining clinical risk factors and the influences of the op- in SR, while this tendency was weak for patients eration, but obviously by the presurgical state of with AF. Hence, the major difference between both the cardiovascular autonomous system. For the de- groups in terms of these parameters is manifested scription of complex phenomena in cardiological by the dynamics of the process during the periop- data, a comprehensive approach, including BRS, classical HRV, and symbolic dynamics, is recom- According to the results of nonlinear dynam- mended. In the present study, analysis of HRV ics, AF patients reveal a higher degree of uni- alone would have resulted in minor differences be- formity in their cardiovascular regulation, which is not disclosed by classical HRV-analysis. For For the future development of a risk stratifi- example, high values of the parameter “Forbid- cation tool, the focus will be on the preoperative den Words” (see Table III) represent a high num- state of the autonomous regulation. The effects of ber of conditions that never appear in the sys- surgery per se seem to equalize any differences be- tem (“forbidden” conditions), which is a direct tween groups. However, the dynamics from pre- indication of uniformity within the cardiovascu- to postoperative may play a role, which has to be lar system.22 AF patients obviously show a ten- dency toward a lower overall dynamic behavior This analysis was not done to add another risk in the preoperative measurements, which may be factor for postoperative AF, but rather to obtain caused by a smaller regulation power and, there- better insight into the contributing mechanisms.
fore, may be less affected by surgery. From these Age, for example, is a very well-known risk factor, results, it can be hypothesized that mechanisms but the term “age” is a fuzzy summary of the en- controlling classical HRV and nonlinear dynam- tity “pathophysiological changes usually related ics are at least partly independent of each other.
to age”33—which, in several patients, may well be There are only few studies about the nonlinear present in earlier years, while in others they are dynamic behavior of the cardiovascular system absent even later in life. Knowing the variety of following surgery. After an initial reduction of clinical risk factors already determined,34 it was complexity, fast recovery is described as well as therefore intended to go one step beyond and to persisting low complexity, depending on the pa- analyze not preexisting clinical conditions, but re- rameters chosen.32 After a look at the results of this lated alterations in the cardiovascular autonomous study, these conflicting findings may be caused by the variability of initial conditions in the differentpatients.
Limitations
It is clearly not the intention of the present Conclusion
study to prove any causality among altered auto- In the present study, the BRS and HRV were nomic function and the occurrence of postopera- found to be changed significantly by heart surgery tive AF, which may be impossible within a clini- with a cardiopulmonary bypass. This is in very cal setting, anyway. We still can hardly speculate if good agreement with the results of a pilot study there is causality, or if measurements of autonomic done in a smaller, more homogeneous patient col- function are only an indicator for forthcoming clin- lective. Furthermore, it was shown that patients ical problems. This study is only intended to be the experiencing AF after the operation presented a description of a new phenomenon, which may be generally lower BRS concerning tachycardic and of clinical significance in the future.
bradycardic regulation. HRV analyses of time and Further studies with larger patient popula- frequency domain parameters and symbolic dy- tions will have to evaluate the predictive value of namics did not reveal any major preoperative BRS for post-operative AF and to define a subset differences between the groups. Postoperatively of the most suitable parameters and their cut-off (which means after surgery, but still before the first points. This information may be used to guide pro- onset of AF), no differences between the groups References
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Source: http://www.pik-potsdam.de/members/kurths/publikationen/2007/291.pdf

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Information for patients following Phacoemulsification (Keyhole Cataract Surgery) Under the care of Mr Goel Pharmacy Department Directorate of Diagnostics & Therapeutics This leaflet has been designed to give you important information about your condition/procedure, and to answer some common queries that you may have. Between your operation and you clinic revie

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J. Chem. Inf. Comput. Sci. 2004, 44, 310-314 Chemical Reactivity as a Tool To Study Carcinogenicity: Reaction between Estradiol and Estrone 3,4-Quinones Ultimate Carcinogens and Guanine† Ph. Huetz,*,‡ E. E. Kamarulzaman,§ H. A. Wahab,§ and J. Mavri*,‡,|Laboratoire de Physique Mole´culaire, UMR CNRS 6624, Faculte´ des Sciences et Techniques, La Bouloie,Universite´ de Franc

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