Eur J Cardiothorac Surg 2005;28:109-113
© 2005 Elsevier Science NL
Nonlinear heart rate variability in CABG patients and the preconditioning effect
Zhong-Kai Wu
a
,
b
,
*
,
Saila Vikman
c
,
Jari Laurikka
b
,
Erkki Pehkonen
b
,
Tiina Iivainen
d
,
Heikki V. Huikuri
e
,
Matti R. Tarkka
b
,
*
a Department of Cardiac Surgery, Affiliated 1st Hospital, Sun Yat-sen University, GuangZhou, China
b Department of Cardiac Surgery, Cardiac Center, Tampere University Hospital, Tampere, Finland
c Department of Cardiology, Cardiac Center, Tampere University Hospital, Tampere, Finland
d Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
e Division of Cardiology, Department of Medicine, University of Oulu, Oulu, Finland
Received 16 January 2005;
received in revised form 10 March 2005;
accepted 11 March 2005.
* Corresponding authors. Address: Clinic of Cardiac Surgery, Tampere University Hospital, 33521 Tampere, Finland. Tel./fax: +358 3 247 5756. (Email: lozhwu{at}uta.fi; Matti.Tarkka{at}pshp.fi).
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Abstract
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Objective: Heart rate variability (HRV) is the most frequently used noninvasive diagnostic method in the assessment of cardiac autonomic control. The clinical relevance of HRV, especially nonlinear HRV in CPB patients has not been well studied. Short brief myocardial ischemia has been reported to influence HRV. We therefore hypothesis that the protective mechanism of ischemic preconditioning (IP) may involve in cardiac autonomic regulation. Methods: Eighty-six CABG patients were randomized into a control and an IP group. The IP patients received two periods of 2-min ischemia followed by 3-min reperfusion by aortic cross-clamped. Holter data were collected in 86 CABG patients before and after surgery. Arrhythmias, linear and nonlinear HRV measures were analyzed. Results: All time and frequency domain HRV variables as well as nonlinear indexes of HRV, the short-term (411 beats) scaling exponent
1, were suppressed significantly after surgery in both study groups. The lower pre- and postoperative exponent
1 predict the higher incidence of postoperative AF and worse postoperative outcome. The suppressed exponent
1 was attenuated in the IP group as compared to controls (P=0.008). No other differences were observed in the changes in linear HRV measures between the groups. IP significantly reduced the incidence of postoperative arrhythmias and improved postoperative outcome. Conclusions: The present findings show that cardiac autonomic regulation is impaired after CABG. Nonlinear HRV exponent
1 is a more sensitive measure to predict the postoperative outcome in CABG patients. IP alleviates the extreme autonomic reactions after surgery, suggesting that cardiac autonomic regulation is involved in the IP protective mechanism.
Key Words: Autonomic nervous system Preconditioning Cardiopulmonary bypass Ischemia/reperfusion Myocardial injury
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1. Introduction
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Heart rate variability (HRV) is the most frequently used noninvasive diagnostic method in assessment of the autonomic control of the heart [113]. Decreased HRV appears to be a predicator of postinfarct arrhythmic complication, hemodynamic instability and mortality [14] and has been under study also in patients undergoing coronary artery bypass grafting (CABG) [510]. Conventionally, time and frequency domain analyses of HRV have been used to measure RR interval variability [2,4]. Since the basic physiologic dynamics of normal sinus rhythm have been shown to have fractal-like features, a number of new HRV measurements based on nonlinear system theory have recently been developed. Nonlinear measures of HRV may reveal subtle abnormalities in cardiac autonomic regulation that may not be detected with traditional time and frequency domain measures [13,1113]. These new methods provide better predictive values of postoperative myocardial ischemia, postoperative atrial fibrillation (AF) and risk stratification in patients undergoing CABG [3,12,13].
Ischemic preconditioning (IP) has been found effective in preserving high-energy phosphate, improving heart performance, reducing cardiac troponin T release, suppressing postoperative arrhythmias and improving postoperative outcome during open-heart surgery [1416]. However, the precise mechanism is as yet unclear. Evidence exists that sympathovagal regulation might be related to the IP protective mechanism. IP is mediated by the sympathetic neurotransmitter release and
1-adrenergic receptor stimulation [17,18]. Acetylcholine, the parasympathetic mediator, is also involved in the IP triggering process [18]. The anti-arrhythmic protection afforded by IP may be mediated by preservation of autonomic function [19]. Other evidence implies that IP may affect sympathovagal activity from the initial to the target effect [20,21]. Brief coronary occlusion may result in severe autonomic reaction as measured by reduced HRV, however, the autonomic reaction after further coronary occlusion has been significantly smaller [2,21,22]. These phenomena imply the importance of cardiac autonomic regulation in the IP protective process. Short-term myocardial ischemia may change the autonomic responses, and we hypothesized that the myocardial protection achieved by IP in CABG patients may also involve cardiac autonomic regulation.
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2. Patients and methods
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The study design was accepted by the Ethical Committee of Tampere University Hospital, Finland, and informed consent was obtained from all patients.
2.1. Patients and study design
Eighty-six consecutive 3-vessel disease patients undergoing CABG were randomized into two groups: a control group and a study (IP) group receiving an IP protocol. Patients with severe calcified ascending aorta, recent myocardial infarction (<3mo), prominent valvular heart diseases, cardiac redo operation, emergency operation and severe noncardiac diseases were excluded from the study. The preoperative characteristics of the patients in the respective groups were similar (Table 1
).
2.1.1. Preconditioning protocol
Cardiopulmonary bypass (CPB) was established and the heart vented. The aorta was then cross-clamped for 2min, followed by 3min reperfusion. The control group also had the pump running for 10min before the routine operation. The temperature was kept normothermic during this period.
2.1.2. Anesthesia, cardiopulmonary bypass (CPB) and surgical technique
A standardized anesthetic technique was used with sufentanil, midazolam and pancuronium. Cardiopulmonary bypass with nonpulsatile perfusion flow (2.22.4l/min per m2) was conducted using membrane oxygenators with arterial line filtration. Mild hypothermia (32°C) was maintained without topical cooling. Blood from the pump reservoir was mixed with crystalloid in a ratio of 4:1, yielding a cardioplegia solution with a 0.21 hematocrite value and 21mmol/l potassium concentration in the initial and 9mmol/l in subsequent doses. In antegrade delivery, cardioplegia was administered at a pressure of 80mmHg and in retrograde 3050mmHg, with a flow of at least 200ml/min. The initial high-potassium cardioplegia was given 1.5min antegrade then 2.5min retrograde, at a temperature of 69°C. One minute was given retrograde and given to RCA and LCX area grafts after each distal anastomosis. Warm cardioplegia (37°C) was given retrograde for 3min before release of cross-clamping. Surgical techniques were the same in all cases. Distal anastomoses were made in the order RCACXLAD. The proximal anastomoses were constructed during cross-clamping. LIMA to LAD was used in all patients.
2.2. Postoperative care
All patients were mechanically ventilated until they had stable hemodynamics and had recovered from the anesthesia. Volume infusion was aimed to maintain filling pressure at least at preoperative level. Pharmacological therapy with inotropes was used to maintain the CI greater than 2.0l/min per m2. ß-Blocker was continued after weaning respirator. The cardiologist on duty was responsible for antiarrhythmic interventions, including medication, pacing and electric cardioversion when needed. Perioperative infarction was diagnosed if any new Q wave appeared with one-third QRS height and for longer than 0.04s or CK-MB passed beyond 100µg/l. The ICU team and cardiologists were blinded in the management of postoperative care.
2.3. Electrocardiographic recordings
Data from 2-channel 24-h electrocardiogram (ECG) Holter recordings (Oxford Medilog 4500) were collected 24h immediately before surgery (preoperative data) and 24h from the 1st postoperative morning (postoperative data). The recordings were analyzed with the Oxford Medilog ECG Replay system (Rel 8.5 version) and manually to detect and quantify arrhythmias and artifacts. The data were sampled digitally and transferred to a microcomputer for the analysis of HRV (Hearts 7 software program, Heart Signal Co., Kempele, Finland).
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3. Analysis of HR variability
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After the ECG data were transferred to the microcomputer, the RR interval series was edited automatically; after this, manual editing was also performed to delete all premature beats including AF and noise. All questionable portions were compared with 2-channel Holter ECGs. Only segments with >80% qualified sinus beats were included. Details of this analysis and filtering method have been described previously [1,11].
3.1. Time and frequency domain measures
Time domain measures determined from normal-to-normal sinus beats included the mean RR interval and its SD (SDNN), Frequency domain HRV analysis was estimated by the fast Fourier method. Ultralow-frequency power (ULF, <0.0033Hz) and very-low-frequency power (VLF, 0.00330.04Hz) were calculated from the entire recording interval. Low-frequency power (LF, 0.040.15Hz), high-frequency power (HF, 0.150.4Hz) components were computed from the segments of 512 RR-intervals and the average values of the entire recordings were used [3].
3.2. Nonlinear analysis of RR data
The same pre-edited RR interval time series that was used for the spectral and time domain analyses of HR variability were also used for calculating nonlinear HRV analysis. A detrended fluctuation analysis (DFA) technique was used to quantify the fractal correlation properties of the RR interval data. This method is a modified root mean square analysis of a random walk. In this study, the short-term (411 beats) scaling exponent
1 was calculated. The scaling exponents were calculated from segments encompassing 8000 beats of the 24-h ECG recording as previously described [1,3,12] and the average values of these segments were used.
3.3. Statistics
Unpaired Student's t-test was used for continuous data (two-tail) and Chi-square test or Fisher's exact test for categorical data when comparing variables between two groups. MannWhitney U-test was used for skewed distributions. Repeated measures analysis of variance was used to test repeated observation variables after the operation. Baseline values were used as a covariant when appropriate in the analysis. Multivariate regression analysis was used to analysis whether exponent
1 is predictive variable of postoperative outcome independent of IP. The level of significance was set at 0.05. Data are presented as mean±SD. Statistical analyses were performed using an SPSS/Win (version 10.0) statistical package program.
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4. Results
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4.1. Outcome of surgery
IP resulted in better postoperative hemodynamic recovery. A significant decrease of postoperative VT episodes and a marginal decrease of postoperative AF episodes were seen in the IP patients. The period of mechanical ventilation was significantly shorter in the IP patients than in the controls. The length of stay in ICU was similar in both groups. More patients in the control group needed postoperative epinephrine support as compared to the IP group. The period of inotropic medication was also marginally shorter in the IP patients than in the controls (Table 2
). There was no perioperative myocardial infarction or early postoperative death in either group. Intra-aortic balloon pump was not required in any patient.
4.2. HRV measurement
Time domain HRV variable SDNN and frequency domain HRV variables, including ULF, VLF, LF and HF, were significantly lower than that obtained preoperatively. Nonlinear HRV variable exponent
1 decreased significantly after surgery also. The reduced linear HRV variables were similar between the IP and the control group. IP resulted in significantly less postoperative changes in exponent
1 (Table 3
).
4.3. The clinical relevance of HRV
Nonlinear HRV, including SDNN, ULF, VLF, LF and HF did not correlate with postoperative administration of inotropes, longer respiratory and ICU treatment period and the patients with AF. Patients with postoperative administration of inotropes, longer ICU treatment period and AF had lower preoperative and postoperative exponent
1. Postoperative exponent
1 in patients with longer respiratory treatment period was significantly lower. Similar results were found using multivariate regression analysis to control the effects of IP (Table 4
).
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5. Discussion
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Time and domain analysis after CABG surgery in the present study were similar with the previous observations, and they support the earlier findings that cardiac autonomic nervous function is impaired after cardiac surgery [510]. The exact mechanism of altered HRV is not known in patients after CABG. In patients with IHD, ischemia has been suggested to destroy the cardiac receptors resulting in altered autonomic regulation [2]. The early drop of HRV after CABG might relate to the acute effects of surgery [10], lesions to autonomic nerve fiber or sinus node injury [5]. Studies also proved that autonomic dysfunction after CABG was not related to anesthesia or medications such as ß-blocker, amiodarone, Ca++ blocker, inotropes and nitrates [3,5,6,9]. The depressed autonomic regulation recovery is accompanied with the improvement of ventricular function, less occurrence of ischemia after CABG and recovery from the direct injury to the vagus nerve or sinus node [9,10].
Nonlinear methods of HRV analysis provide information about heart rate dynamics in ways which are not evident in traditional time and frequency domain measures [13,1113]. Reduced exponent
1 have been showed to be predictors of mortality [2], onset of AF [1,12] and VT [11] in coronary heart disease. A more random and less fractal-like HR behavior, as measured by decreased exponent
1 is associated with more myocardial ischemic episodes and complicated clinical course of patients after CABG [3,13]. Such changes may occur several hours before the onset of ischemia [13]. These changes may contribute to the sympathovagal interaction, as the consequences of high norepinephrine level after CABG [23,24]. Traditional HRV measurement has been reported not to correlate with myocardial injury and clinical outcome in patients undergoing CABG [3,5]. In the present study, the nonlinear HRV measures after CABG resembles the previous findings in patients after CABG [3,13]. Our data suggested that less random and more fractal-like HR behavior in the CABG patients resulted in better postoperative outcome, such as less inotropic support, shorter respiratory and ICU treatment periods and less postoperative AF.
The present findings showed that IP reduced postoperative arrhythmias and improved postoperative outcome. IP also alleviated extreme cardiac autonomic reactions after surgery, manifested as less postoperative changes of exponent
1. Previous studies have shown that extreme autonomic reaction may lead to hemodynamic instability and fatal arrhythmia [21]. The decreased exponent
1 suggest more random and less fractal-like HR dynamics after surgery. Such changes were reported to be associated with myocardial ischemic episodes and complicated clinical course in patients after CABG [3,13]. Thus, blunting of both of these extreme autonomic reactions by IP may be an advantageous form of adaptation [21]. The results imply that the protective IP mechanism might involve the better cardiac autonomic regulation of HR immediately after surgery.
Whether cardiac autonomic regulation is related to the protective mechanism of IP has not been studied. On the other hand, previous investigations implied that short brief myocardial ischemia might change HRV and subsequently attenuate the HRV changes in the following myocardial ischemic event, similar with the present finding. IP resulted in better preservation of the efferent sympathetic and parasympathetic nerve fibers traversing the ischemic region [19]. Acute coronary occlusion also results in severe autonomic reaction [2,21]. Preceding short vessel occlusionreperfusion cycle attenuate HR reaction, especially vagal reaction, during subsequent occlusion. The decreased HRV reaction was at the receptor level or by the modulation of the central nervous system [21]. Parasympathetic tone, measured by HF, adapt to myocardial ischemia in patients undergoing PTCA, suggesting that autonomic regulation may play an important role in IP in humans [22]. As the result, IP may increase the VT threshold [25], as to reduce the incidence of ischemia reperfusion arrhythmia [16].
5.1. Study limitations
The efferent vagal activity is a major contributor to HF component. LF is a quantitative marker of sympathetic and parasympathetic modulation. Time domain is mainly thought to be parasympathetic [1,5]. On the other hand, the physiological nonlinear HRV have not been well defined. Nonlinear HRV analysis differs from the traditional measures of HRV because they are not designed to assess the magnitude of the variability, but rather the quality properties of the signal [3]. They are the result of a complex interaction between autonomic tone, sensory input, central influence, vasomotor regulation, and target organ responsiveness [2]. Further research on the physiological background of these new HR variability indices and on their clinical usefulness in various settings will be needed. In the present study, we showed that cardiac autonomic regulation was involved in the IP protective mechanism, but we do not know yet at which level IP preserves the autonomic function and how it consequently protect the heart.
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Acknowledgments
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The study was supported by the Research Foundation of Tampere University Hospital, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation and Finnish Foundation for Cardiovascular Research.
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