IJCA-18031; No of Pages 7 International Journal of Cardiology xxx (2014) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting Seung-Jung Park a, Young Keun On a, June Soo Kim a,⁎, Dong Seop Jeong b, Wook Sung Kim b, Young Tak Lee b a b
Department of Internal Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Thoracic and Cardiovascular Surgery, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 10 February 2014 Accepted 12 April 2014 Available online xxxx Keywords: Heart rate turbulence Cardiac autonomic function Coronary artery bypass graft surgery Atrial fibrillation
a b s t r a c t Background: Cardiac autonomic dysfunction reportedly contributes to the AF triggering and maintenance. Heart rate turbulence (HRT) is a promising noninvasive measure of cardiac autonomic function. We investigated whether ambulatory ECG-based HRT measurement could predict in-hospital new-onset atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. Methods: HRT onset (TO) and slope (TO) were prospectively measured from 24-h Holter recording in 113 consecutive patients prior to CABG. Abnormal HRT was defined as at least one abnormal value in TO (N 0%) and TS (b2.5 ms/RR). Results: Patients with abnormal HRT (n = 60) showed a significantly higher AF incidence (47% versus 21%, P = 0.005) and AF burden (29 ± 9 versus 7 ± 5 h, P = 0.043) than those with normal HRT (n = 53). Abnormal HRT were identified as independent predictors for the new-onset postoperative AF. During the follow-up period (12.0 ± 10.5 months), the abnormal HRT group showed a worse prognosis versus the normal HRT group regarding the AF recurrence/postoperative stroke (P = 0.018). Additionally, the postoperative AF incidence, in-hospital AF burden, and the rate of AF recurrence/postoperative stroke gradually elevated as the number of abnormal HRT values increased from 0 to 2. Conclusions: Preoperative abnormal HRT was significantly associated with worse short-term (in-hospital new-onset AF) and long-term outcomes (post-discharge AF recurrence/postoperative stroke) after CABG surgery. Additional studies incorporating preventive interventions depending on the preoperative HRT results might be worthwhile in this patient group. © 2014 Elsevier Ireland. Ltd
1. Introduction Atrial fibrillation (AF) is the most common arrhythmic complication after coronary artery bypass graft (CABG) surgery and is often associated with an increased risk of congestive heart failure, in-hospital stroke, prolongation of hospital stay, and rehospitalization [1–4]. Experimental and clinical studies show that impaired cardiac autonomic function contributes to the triggering and maintenance of AF [5–7]. Heart rate turbulence (HRT), a noninvasive electrocardiographic measure of cardiac autonomic function, has been introduced as a promising risk stratifier of cardiovascular death or sudden cardiac death after myocardial infarction (MI) [8–10]. However, no prospective study has described the prognostic value of HRT parameters for predicting new-onset AF in patients undergoing CABG surgery. Therefore, this prospective observation study was designed to evaluate whether the preoperative abnormal HRT could predict in-hospital ⁎ Corresponding author at: Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135710, Republic of Korea. Tel.: +82 2 3410 3414; fax: +82 2 3410 3417. E-mail address: [email protected] (J.S. Kim).
occurrence of AF after CABG surgery. We also investigated association between the preoperative abnormal HRT and recurrence of AF and AF-related embolic stroke during the follow-up period. 2. Materials and methods 2.1. Patients population. We prospectively enrolled 172 consecutive patients undergoing elective CABG surgery from May 2010 to December 2012 at the Samsung Medical Center. The main exclusion criteria were urgent/emergent surgery in which HRT examination was not feasible, pre-existing (permanent, persistent, or paroxysmal) AF rhythm or pacemaker rhythm prior to CABG, enrollment into other clinical studies, combined maze procedure, and patient's refusal. The study protocol was approved by the institutional review board of Samsung Medical Center and all subjects gave their informed consent for participation. 2.2. Definition of abnormal HRT values and measurement of HRT HRT represents a biphasic change of heart rate (HR) following premature ventricular contractions (PVCs): initial acceleration and subsequent deceleration of HR, in other words, initial decrease and subsequent increase in sinus RR interval. The two phases of HRT (the early acceleration and late deceleration of HR) are quantified by two numerical values, namely, the turbulence onset (TO) and the turbulence slope (TS), respectively [11,12]. TO was defined as the percentage change in the post-PVC RR intervals against
http://dx.doi.org/10.1016/j.ijcard.2014.04.130 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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the pre-PVC RR intervals. TS was defined as the maximum positive regression slope obtained over any 5 consecutive sinus RR intervals within the first 15 sinus RR intervals following the PVC. Therefore, in the normal subjects, the initial brief acceleration of HR after the PVC is represented as negative TO, and the subsequent HR deceleration is characterized by positive TS. For the present study, the values of TO N 0% and TS b 2.5 ms/RR interval were defined abnormal, respectively, as in the previous studies [11,12]. Patients were considered having normal HRT when both TO and TS were measured normal whereas those with at least one abnormal values were considered having abnormal HRT. Additionally, patients were graded into 3 groups according to the combined values of TO and TS; HRT0 group (both TO and TS were normal), HRT1 group (either TO or TS was abnormal), and HRT2 group (both TO and TS were abnormal). Ambulatory electrocardiograms were recorded 1 to 3 days prior to elective CABG surgery using an ambulatory 3-lead SEER Light Digital Holter monitor with a sampling rate of 125 samples per second (GE Healthcare Inc, Milwaukee, WI, USA), and HRT values were analyzed using a MARS 8000 Holter analyzer (GE Healthcare Inc, Milwaukee, WI, USA). For more accurate assessment of the HRT pattern, averaging responses to multiple PVCs (≥5) is needed because the HRT pattern after the PVCs can be affected by HR variability from other causes. Thus, we tried to perform Holter recordings at least 20 h prior to CABG surgery and any Holter tracing with less than 5 suitable PVCs were discarded [12]. In addition, to incorporate only suitable PVCs in the HRT assessment, a usually recommended filter settings [12,13] were adopted (Supplementary Table 1). Additionally, several time- and frequency-domain HR variability (HRV) parameters were also measured using the same system; standard deviation of all normal-to-normal RR intervals (SDNN), root mean square successive difference measures (rMSSD), low-frequency power (LF), high-frequency (HF), and LF/HF ratio.
3. Results 3.1. Characteristics of patients During the enrollment period, 172 consecutive patients underwent 24-h Holter recording prior to elective CABG surgery. Of these, 59 patients were excluded for the following reasons; 55 for insufficient number of suitable PVCs (b 5) during the Holter recordings, 3 for newly detected AF episodes during the Holter recordings prior to surgery, and 1 for premature termination of Holter recording due to aggravation of patent's symptom. Therefore, HRT measurement was possible in 113 patients and they were incorporated into the final analysis (Fig. 1). Median (IQR) age of the 113 patients was 67 (58–71) years, and the proportion of male patients was 72%. Patients with 3 vessel disease accounted for 72% of total population. Twelve patients (11%) had a history of previous coronary artery revascularization. The median (IQR) left ventricular (LV) ejection fraction (EF) and left atrial volume index (LAVi) at baseline were 58% (48–66%) and 37 (31–47) ml/m2, respectively. Off-pump CABG surgery was performed for 88 patients (78%), and 9 patients underwent combined valve surgery; 4 aortic valve replacement, 3 mitral valvuloplasty, and 5 mitral annuloplasty.
2.3. CABG surgery Pretreatment with morphine and diazepam (0.1 mg/kg) was performed for all patients prior to CABG surgery. No anti-arrhythmic agents including amiodarone, sotalol, intravenous beta-blockers, or corticosteroids were given for arrhythmia prophylaxis except potassium and magnesium supplementation, which was started in the operating room. The standard regimen of anesthesia were used for all patients. For anesthesia induction, etomidate (0.3 mg/kg), midazolam (0.1 mg/kg), and sufentanil (1–2 μg/kg) were used. Muscle relaxation was achieved with rocuronium bromide (0.6 mg/kg). For anesthesia maintenance, isoflurane, etomidate, and sufentanil were given. Midline sternotomy with standard techniques of on- or off-pump CABG surgery was carried out for all patients. The type of surgery and procedural strategies were determined by the experienced surgeon. Internal mammary artery grafts with or without saphenous vein grafts were used in all patients. Heparin (150 IU/kg) was given to obtain an activated clotting time more than 300 s. After the anastomoses were completed, protamine sulfate was administered to reverse the heparin effect. Aspirin was started within the first 24 h after surgery in all patients. Weaning from intravenous inotropic agents was guided according to standard hemodynamic criteria. Beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, amiodarone, or warfarin were used during the postoperative period when clinically indicated [14]. 2.4. Post-CABG rhythm monitoring and study outcomes The primary outcome was the incidence of new-onset postoperative AF and AF burden during the hospital stay. Monitoring the postoperative rhythm was performed continuously before discharge with the onset and termination of AF recorded on medical flow chart. Postoperative AF was defined as any documented AF N 5 min in duration or AF episodes requiring electrical cardioversion for symptomatic or hemodynamic compromise after CABG surgery. AF burden was defined as the total duration of all the AF episodes in each patients and calculated by summing up each duration of in-hospital AF episodes. The secondary outcomes were AF recurrence and postoperative stroke during the longterm follow-up. Recurrence of AF was evaluated by taking serial 12-lead ECGs (1, 3, 6, 12, and 24 months) and 24-h Holter monitor exam (12 and 24 months). If patients reported symptoms suggesting recurrence of AF at any time, 12-lead ECG and 24-h Holter monitoring were repeated. Postoperative stroke was defined as the development of a new focal neurologic deficit lasting N24 h with confirmation by computed tomographic or magnetic resonance imaging scan after the surgery. 2.5. Statistical analysis Continuous data are presented as medians with interquartile ranges (IQR) and categorical data as number with percentages. Continuous variables were compared with Mann–Whitney test and categorical variables with the Fisher's exact test. Predictors for new-onset AF after the CABG surgery were evaluated using univariate and multiple logistic regression analyses. After univariate analysis, the variables attaining a P value b 0.05 were entered into a multiple logistic regression model. Event (AF recurrence or stroke)-free survival was estimated by Kaplan–Meier analysis and the log-rank test was applied to evaluate differences between survival curves. Correlations between the grade of HRT abnormality and AF incidence or AF burden were evaluated using linear-bylinear association and Spearman's rho test for trend. All statistical analyses were performed using PASW Statistics 18 software for Microsoft (SPSS Inc., Chicago, IL, USA). All P values were two-sided and results with a P value less than 0.05 were considered statistically significant.
3.2. Patients with normal versus abnormal HRT values Preoperative median values (IQR) for TO and TS were − 0.48% (−1.43% to 0.32%) and 3.52 (1.86 to 8.11) ms/RR interval, respectively. Of the 113 patients, abnormal TO (N0%) and abnormal TS (b2.5 ms/RR interval) values were noted in 37 and 40 patients, respectively. Seventeen patients showed abnormal results in both values. Therefore, according to the definition, 60 patients were categorized as the abnormal HRT (at least one abnormal value in TO and TS) group and the remaining 53 as the normal HRT (both TO and TS normal) group (Fig. 1). Representative examples of normal and abnormal HRT were shown in Fig. 2. The baseline characteristics of patients with normal and abnormal HRT values are compared in Table 1. Patients with abnormal HRT revealed a higher prevalence of female gender, congestive heart failure, and diabetes than those with normal HRT values. Corrected QT interval, LAVi, and serum level of N-terminal prohormone brain natriuretic peptide (NT-proBNP) were measured significantly greater in the abnormal HRT compared to the normal HRT group. Several HRV variables including SDNN, LF, and LF/HF ratio were lower in the abnormal HRT group. However, there was no significant difference between the two groups in terms of previous stroke history, severity of coronary or valve disease, LV EF, and baseline medications (Tables 1 and 2). Proportions of patients who underwent off-pump CABG or combined valve surgery were not also significantly different between the two groups. 3.3. Clinical outcomes depending on the HRT values During the index hospitalization, postoperative AF episodes occurred in 39 (35%) of 113 patients. Postoperative stroke affected 3 (7.7%) of 39 patients with postoperative AF. Mean AF burden (total duration of all AF episodes) was calculated 22 ± 7 h. Electrical cardioversion was required in 5 patients and intravenous amiodarone was used in 20 patients. Postoperative AF was noted more frequently in the abnormal HRT than normal HRT group (28/60, 47% versus 11/53, 21%; P = 0.005, Fig. 3) and AF burden of the abnormal HRT group was significantly greater than that of the normal HRT group (29 ± 9 versus 7 ± 5 h, P = 0.043). Electrical cardioversion was performed only in patients with abnormal HRT values. There was a trend toward a longer hospital duration in the abnormal HRT group (11 ± 10 versus 9 ± 8 h, P = 0.199). Only 1 patient with preoperative abnormal HRT was discharged in AF, whereas the remaining 112 patients in sinus rhythm. Specific medications at discharge showed no significant difference between the two groups (Table 2).
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Fig. 1. Flow chart of the present study. AF = atrial fibrillation; CABG = coronary artery bypass graft; HRT = heart rate turbulence; PVC = premature ventricular contraction; TO = turbulence onset; TS = turbulence slope. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
During the follow-up period (12.0 ± 10.5 months) after discharge, 9 (8%) of the 113 patients experienced secondary outcomes: 7 patients had recurrent AF requiring standard treatment (anticoagulation, rate, or rhythm management) and additional strokes were observed in 2 patients. The secondary outcomes developed only in patients who had shown postoperative AF during the index hospitalization (9/39, 23% versus 0/74, 0%; P b 0.001). Regarding the secondary outcomes as well, the abnormal HRT group showed a worse prognosis versus the normal HRT group (Fig. 4).
3.4. Independent predictors associated with adverse outcomes. To assess the independent predictors associated with postoperative AF, multivariate logistic regression models were constructed with risk variables attaining P values b 0.05 on univariate analysis (Table 3). Heart failure history, LV EF b 50%, LAVi ≥ 40 ml/m2, and abnormal HRT were significantly associated with the development of postoperative AF on univariate analysis. Among these parameters, abnormal HRT
Fig. 2. Representative examples of normal and abnormal HRT. SR = sinus rhythm; other abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Table 1 Comparison of baseline characteristics.
Demographics Age, years Male gender, n (%) Congestive heart failure, n (%) Hypertension, n (%) Diabetes, n (%) Chronic kidney disease, n (%) Previous stroke or TIA, n (%) Previous MI, n (%) Previous PCI or CABG, n (%) 3 vessel disease, n (%) Electrocardiographic or 24-h Holter data Average heart rate, bpm QRS duration, ms QTc interval, ms Premature ventricular contraction, n SDNN rMSSD Low-frequency power High-frequency power Low-frequency/high-frequency ratio Echocardiographic parameters LV ejection fraction,% Left atrial volume index, ml/m2 Moderate to severe VHD, n (%) Laboratory values hs-CRP, mg/dl NT-proBNP, pg/ml Operations Off-pump CABG, n (%) Combined valve surgery, n (%)
Normal HRT (n = 53)
Abnormal HRT (n = 60)
P value
65 (56–71) 43 (81) 1 (2) 42 (79) 18 (34) 8 (15) 5 (9) 3 (6) 5 (9) 39 (74)
68 (63–72) 38 (63) 11 (18) 42 (70) 39 (65) 18 (30) 9 (15) 1 (2) 7 (12) 42 (71)
0.072 0.039 0.005 0.288 0.001 0.075 0.407 0.340 0.767 0.835
69 (65–74) 96 (90–105) 418 (409–438) 64 (19–151) 89 (71–100) 20 (15–24) 12.6 (9.9–15.9) 7.9 (6.5–9.6) 1.6 (1.3–2.0)
72 (65–78) 92 (86–100) 438 (420–534) 71 (21–387) 81 (64–93) 20 (15–24) 10.7 (6.8–13.5) 7.6 (5.2–11.1) 1.3 (1.0–1.7)
0.251 0.071 0.004 0.173 0.032 0.892 0.005 0.366 0.001
59 (50–67) 35 (29–43) 3 (6)
58 (44–66) 40 (34–53) 5 (8)
0.146 0.002 0.721
0.12 (0.04–0.41) 1150 (400–4125)
0.26 (0.07–0.86) 2550 (675–8600)
0.055 0.004
41 (77) 3 (6)
47 (78) 6 (10)
1.000 0.498
CABG = coronary artery bypass graft surgery; hs-CRP = high-sensitivity C-reactive protein; HRT = heart rate turbulence; LV = left ventricular; MI = myocardial infarction; NT-proBNP = N-terminal prohormone brain natriuretic peptide; PCI = percutaneous coronary intervention; QTc = corrected QT; rMSSD = root mean square successive difference measures; SDNN = standard deviation of normal-to-normal beat intervals; TIA = transient ischemic attack; VHD = valvular heart disease.
and LAVi ≥ 40 ml/m2 were identified as independent predictors for the development of postoperative AF. 3.5. Correlation between the grade of HRT abnormality and clinical outcomes
AF burden (r = 0.310, P = 0.001) and the duration of hospital stay (r = 0.184, P = 0.050). In a similar way, regarding the secondary endpoints, the HRT2 group showed the worst prognosis whereas the HRT0 group the most benign course (Fig. 5B). 4. Discussion
To assess the clinical outcomes depending on the grade of HRT abnormality, we divided the 113 patients into 3 groups according to the combined values of TO and TS; HRT0 group (n = 53, both TO and TS were normal), HRT1 group (n = 43, either TO or TS was abnormal), and HRT2 group (n = 17, both TO and TS were abnormal). The incidence of postoperative AF gradually increased as the number of abnormal HRT values increased from 0 to 2 (P for trend = 0.001, Fig. 5A). The number of abnormal HRT values was also positively correlated with postoperative
4.1. New findings The present study is the first to show a significant association between the preoperative HRT abnormality and the increased risk of
Table 2 Comparison of medications.
Baseline Aspirin, n (%) Clopidogrel, n (%) ACEI or ARB, n (%) Statin, n (%) Beta-blocker, n (%) At discharge Aspirin, n (%) Clopidogrel, n (%) Warfarin, n (%) ACEI or ARB, n (%) Statin, n (%) Beta-blocker, n (%) Amiodarone, n (%)
Normal HRT (n = 53)
Abnormal HRT (n = 60)
P value
34 (64) 9 (17) 17 (32) 27 (51) 17 (32)
36 (60) 12 (20) 11 (18) 26 (43) 21 (35)
0.701 0.810 0.126 0.454 0.842
53 (100) 31 (59) 3 (6) 11 (36) 42 (79) 48 (91) 4 (8)
58 (97) 27 (45) 7 (12) 8 (42) 49 (82) 51 (85) 5 (8)
0.497 0.188 0.331 0.566 0.814 0.407 1.000
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HRT = heart rate turbulence.
Fig. 3. In-hospital outcomes depending on preoperative HRT values. *AF burden was defined as the total duration of all the AF episodes in each patient. Abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Fig. 4. Kaplan–Meier event-free curves for the secondary outcomes (AF recurrence and postoperative stroke) based on preoperative HRT values. Abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
postoperative new-onset AF in patients undergoing CABG surgery. Although there have been many studies dealing with clinical implications of HRT, most of the previous evaluations primarily focused on the risk of cardiac death, ventricular tachyarrhythmia, and sudden cardiac death after acute MI [7–9]. One retrospective data suggested that HRT-based autonomic dysfunction was associated with the development of postoperative AF in 100 patients who underwent cardiac valve or CABG surgery [15]; however, long-term outcomes were not presented. In contrast, our study provided prospectively short- and long-term prognostic value of HRT measurement; in our results, approximately 50% of patients undergoing CABG surgery had preoperative autonomic dysfunction suggested by HRT analysis and patients with abnormal HRT values showed more than two times increased risk of developing postoperative AF. Abnormal HRT was also independently associated with postoperative new-onset AF even after adjusted for relevant clinical and echocardiographic parameters. During the follow-up period as well, AF recurrence and stroke developed more frequently in patients with preoperative abnormal HRT than those with normal HRT. In addition, the short- and long-term clinical outcomes became gradually worse as the grade of HRT abnormality increased, interestingly, which findings are coherent
Fig. 5. Clinical outcomes based on the grade of HRT abnormality. Patients were divided into 3 groups based on the combined values of TO and TS; HRT0 group (both TO and TS were normal), HRT1 group (either TO or TS was abnormal), and HRT2 group (both TO and TS were abnormal). (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Table 3 Predictors for postoperative AF. Characteristics
Age ≥ 65 years, n (%) Male gender, n (%) CHF, n (%) Diabetes, n (%) QTc interval, ms LV EF b 50%, n (%) LAVi ≥ 40 ml/m2, n (%) hs-CRP, mg/dl NT-proBNP, pg/ml Beta-blocker, n (%) Statin, n (%) OPCABG, n (%) TO, % TS, ms/RR Abnormal HRT, n (%)
Non-PAF
PAF
(n = 74)
(n = 39)
P value
Univariate analysis
43 (58) 53 (72) 4 (5) 36 (49) 421 (409–453) 18 (25) 19 (26) 0.11 (0.04–0.45) 139 (71–443) 24 (32) 35 (47) 61 (82) −0.97 (−2.02 to −0.02) 3.9 (2.2–10.2) 32 (43)
26 (67) 28 (72) 8 (21) 21 (54) 436 (423–449) 16 (43) 25 (68) 0.34 (0.12–1.18) 795 (71–1799) 14 (36) 18 (46) 27 (69) −0.01 (−0.49 to 0.68) 2.4 (1.1–4.2) 28 (72)
0.422 1.000 0.022 0.693 0.052 0.053 b0.001 0.003 0.003 0.843 1.000 0.152 b0.001 0.003 0.005
Multivariate analysis
Odds ratio (95% CI)
P value
1.01 (0.43–2.39) 4.45 (1.25–15.9) 1.23 (0.57–2.68) 1.01 (0.99–1.02) 2.33 (1.01–5.40) 6.03 (2.54–14.3) 0.99 (0.98–1.01) 1.00 (1.00–1.00)
0.984 0.021 0.600 0.213 0.049 b0.001 0.613 0.157
1.23 (1.01–1.50) 0.897 (0.81–0.99) 3.34 (1.45–7.70)
0.045 0.029 0.005
Odds ratio (95% CI)
P value
1.77 (0.37–8.46)
0.475
1.32 (0.45–3.87) 4.58 (1.85–11.4)
0.611 0.001
2.64 (1.03–6.80)
0.044
CHF = congestive heart failure; EF = ejection fraction; OPCABG = off-pump CABG; TO = turbulence onset; TS = turbulence slope and other abbreviations as in Table 1.
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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with several previous studies reporting the worst prognosis in patients with both abnormal results in TO and TS [8,16]. 4.2. Abnormal HRT and the risk of postoperative AF Although the exact physiologic mechanisms of the PVC-induced HRT are not fully elucidated, baroreflex-medicated cardiac autonomic function is considered to play a central role [12]. Transient BP reduction caused by ineffective PVCs activates aortic and carotid baroreceptors, which induces vagal inhibition leading to initial HR acceleration. However, 10 to 20 beats later, the initial HR acceleration is followed by a subsequent HR deceleration to the pre-PVC level by vagal reactivation. Therefore, abnormal HRT values (TO N 0% and/or TS b 2.5 ms/RR) represent cardiac autonomic dysfunction; abnormally elevated vagal tone might blunt the early HR increase resulting in a positive TO value (N 0%), whereas abnormally enhanced sympathetic tone might attenuate the late HR decrease leading to a lower TS value (b2.5 ms/RR). Then this cardiac autonomic dysfunction/imbalance is known to contribute to the triggering and maintenance of postoperative or post-MI AF [5,17,18]; vagal activation shortens the atrial refractory period making AF wavelengths smaller and depolarized atrial tissue recover rapidly. Therefore, multiple AF wave fronts can find remaining excitable atrial tissue on and on. Enhanced sympathetic stimulation can increase automaticity of atrial ectopic focus [19]. In post-MI patients, disturbances in the cardiac autonomic regulation suggested by abnormal HRV or HRT parameters were associated with increased risk of new-onset AF independently of conventional clinical risk variables [18]. Autonomic modulation using botulinum toxin (for vagal tone), beta blocking agents (for sympathetic tone), and ablation of ganglionic plexi (for vagal/sympathetic tone) has been suggested as an effective method to reduce postoperative AF in many preclinical experiments and clinical trials [20–22]. On the other hand, impaired cardiac autonomic function may be a marker of more severe cardiovascular dysfunction, which itself could make patients more susceptible to the postoperative AF; HRT values are shown to be affected by LV systolic dysfunction and advanced age [12]. Indeed in our data, LV EF was lower and NT-proBNP level was significantly higher in patients with abnormal HRT versus those with normal HRT. 4.3. Clinical implications Pretreatment with several medications such as beta-blockers, statin, ACEI, and amiodarone has been effective for reducing the postoperative AF in patients undergoing CABG surgery [21,23–25]. Then most of the patients undergoing CABG surgery often have indications for these medications due to other conditions including hypertension, hypercholesterolemia, and diabetes. However, amiodarone use is not always straightforward as the other agents due to its potential side effects [25]. Therefore, stratification of patients at higher risk for postoperative AF using preoperative HRT measurement might be useful in deciding whether to perform an amiodarone prophylaxis. There are several other methods by which cardiac autonomic dysfunction can be evaluated such as HRV and baroreflex sensitivity using phenylnephrine infusion [26]. However, phenylnephrine, an alpha-adrenergic agent, might also aggravate myocardial ischemia by elevating blood pressure especially in patients with unstable angina. In contrast, ambulatory ECG-based HRT measurement is easy to perform and feasible even in patients who cannot tolerate exercise or vasoactive drug challenge (e.g., phenylnephrine). Additionally, invasive procedure such as intravenous cannulation is not required. HRV measurement could be limited by frequent premature atrial/ventricular contractions. However, the occurrence of premature beats is a precondition for HRT measurement, Therefore, both HRV and HRT, as good markers of autonomic dysregulations, could be measured simultaneously using a 24-h Holter recordings and used in a complimentary way to improve a discriminatory power for post-CABG AF.
4.4. Study limitations The present study has the limitations inherent to the way HRT values are measured; HRT evaluation is not possible in patients without PVCs. It cannot be measured in patients with persistent/permanent AF or pacemaker rhythm as well. In addition, patients who require emergent/ urgent CABG surgeries may be ineligible. The incidence of postoperative AF in our data was higher than those from other reports [23,27], therefore, the same results might not always be found in other study populations and our results need to be interpreted with caution. The higher incidence of AF may be related, at least partly, to the fact that 30% of our patients underwent on-pump CABG or combined valve surgery that are well known to increase the rate of post-CABG AF. Efficacy of preventive interventions depending on the HRT abnormality was not evaluated in our study. Therefore, more prospective studies with preventive approaches are needed to validate our findings more definitely. 5. Conclusion Preoperative abnormal HRT was identified as an independent predictor of postoperative in-hospital new-onset AF in patients undergoing CABG surgery. It was also significantly associated as worse long-term outcomes; AF recurrence and postoperative stroke. These short- and long-term risks were gradually elevated as the grade of HRT abnormality increased. Additional prospective studies incorporating preventive interventions depending on the preoperative HRT results may be worthwhile to show the clinical implication of the HRT measurement more definitely in this patient group. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.04.130. Acknowledgements The authors are grateful for the invaluable contributions from the following specialists at the Samsung Medical Center: Soo-Young Cho, RN. and Soo-Youn Kim, Ms. for data collection. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–73. [2] Lahtinen J, Biancari F, Salmela E, et al. Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:1241–4. [3] Mariscalco G, Klersy C, Zanobini M, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation 2008;118:1612–28. [4] Song SW, Sul SY, Lee HJ, Yoo KJ. Comparison of the radial artery and saphenous vein as composite grafts in off-pump coronary artery bypass grafting in elderly patients: a randomized controlled trial. Korean Circ J 2012;42:107–12. [5] Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264–74. [6] Bauernschmitt R, Malberg H, Wessel N, et al. Autonomic control in patients experiencing atrial fibrillation after cardiac surgery. Pacing Clin Electrophysiol 2007;30:77–84. [7] Dimmer C, Tavernier R, Gjorgov N, Van Nooten G, Clement DL, Jordaens L. Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 1998;82:22–5. [8] Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999;353:1390–6. [9] Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (the Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002;89:184–90. [10] Mäkikallio TH, Barthel P, Schneider R, et al. Prediction of sudden cardiac death after acute myocardial infarction: role of Holter monitoring in the modern treatment era. Eur Heart J 2005;26:762–9. [11] Hoshida K, Miwa Y, Miyakoshi M, et al. Simultaneous assessment of T-wave alternans and heart rate turbulence on Holter electrocardiograms as predictors for serious cardiac events in patients after myocardial infarction. Circ J 2013;77:432–8.
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
S.-J. Park et al. / International Journal of Cardiology xxx (2014) xxx–xxx [12] Bauer A, Malik M, Schmidt G, et al. Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use: International Society for Holter and Noninvasive Electrophysiology Consensus. J Am Coll Cardiol 2008;52:1353–65. [13] Secemsky EA, Verrier RL, Cooke G, et al. High prevalence of cardiac autonomic dysfunction and T-wave alternans in dialysis patients. Heart Rhythm 2011;8:592–8. [14] Shin HW, Kim YN, Bae HJ, et al. Trends in oral anticoagulation therapy among Korean patients with atrial fibrillation: the Korean Atrial Fibrillation Investigation. Korean Circ J 2012;42:113–7. [15] Ovreiu M, Nair BG, Xu M, et al. Electrocardiographic activity before onset of postoperative atrial fibrillation in cardiac surgery patients. Pacing Clin Electrophysiol 2008;31:1371–82. [16] Barthel P, Schneider R, Bauer A, et al. Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation 2003;108:1221–6. [17] Amar D, Zhang H, Miodownik S, Kadish AH. Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation. J Am Coll Cardiol 2003;42:1262–8. [18] Jons C, Raatikainen P, Gang UJ, et al. Autonomic dysfunction and new-onset atrial fibrillation in patients with left ventricular systolic dysfunction after acute myocardial infarction: a CARISMA substudy. J Cardiovasc Electrophysiol 2010;21:983–90. [19] Oral H, Crawford T, Frederick M, et al. Inducibility of paroxysmal atrial fibrillation by isoproterenol and its relation to the mode of onset of atrial fibrillation. J Cardiovasc Electrophysiol 2008;19:466–70.
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[20] Oh S, Choi EK, Zhang Y, Mazgalev TN. Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation. Circ Arrhythm Electrophysiol 2011;4:560–5. [21] Budeus M, Feindt P, Gams E, et al. Beta-blocker prophylaxis for atrial fibrillation after coronary artery bypass grafting in patients with sympathovagal imbalance. Ann Thorac Surg 2007;84:61–6. [22] Doll N, Pritzwald-Stegmann P, Czesla M, et al. Ablation of ganglionic plexi during combined surgery for atrial fibrillation. Ann Thorac Surg 2008;86:1659–63. [23] Song YB, On YK, Kim JH, et al. The effects of atorvastatin on the occurrence of postoperative atrial fibrillation after off-pump coronary artery bypass grafting surgery. Am Heart J 2008;156(373):e9-16. [24] Ozaydin M, Dede O, Varol E, et al. Effect of renin-angiotensin aldosteron system blockers on postoperative atrial fibrillation. Int J Cardiol 2008;127:362–7. [25] Mitchell LB, Exner DV, Wyse DG, et al. Prophylactic oral amiodarone for the prevention of arrhythmias that begin early after revascularization, valve replacement, or repair: PAPABEAR: a randomized controlled trial. JAMA 2005;294:3093–100. [26] La Rovere MT, Pinna GD, Raczak G. Baroreflex sensitivity: measurement and clinical implications. Ann Noninvasive Electrocardiol 2008;13:191–207. [27] Kinoshita T, Asai T, Ishigaki T, Suzuki T, Kambara A, Matsubayashi K. Preoperative heart rate variability predicts atrial fibrillation after coronary bypass grafting. Ann Thorac Surg 2011;91:1176–81.
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting Seung-Jung Park a, Young Keun On a, June Soo Kim a,⁎, Dong Seop Jeong b, Wook Sung Kim b, Young Tak Lee b a b
Department of Internal Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Thoracic and Cardiovascular Surgery, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 10 February 2014 Accepted 12 April 2014 Available online xxxx Keywords: Heart rate turbulence Cardiac autonomic function Coronary artery bypass graft surgery Atrial fibrillation
a b s t r a c t Background: Cardiac autonomic dysfunction reportedly contributes to the AF triggering and maintenance. Heart rate turbulence (HRT) is a promising noninvasive measure of cardiac autonomic function. We investigated whether ambulatory ECG-based HRT measurement could predict in-hospital new-onset atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. Methods: HRT onset (TO) and slope (TO) were prospectively measured from 24-h Holter recording in 113 consecutive patients prior to CABG. Abnormal HRT was defined as at least one abnormal value in TO (N 0%) and TS (b2.5 ms/RR). Results: Patients with abnormal HRT (n = 60) showed a significantly higher AF incidence (47% versus 21%, P = 0.005) and AF burden (29 ± 9 versus 7 ± 5 h, P = 0.043) than those with normal HRT (n = 53). Abnormal HRT were identified as independent predictors for the new-onset postoperative AF. During the follow-up period (12.0 ± 10.5 months), the abnormal HRT group showed a worse prognosis versus the normal HRT group regarding the AF recurrence/postoperative stroke (P = 0.018). Additionally, the postoperative AF incidence, in-hospital AF burden, and the rate of AF recurrence/postoperative stroke gradually elevated as the number of abnormal HRT values increased from 0 to 2. Conclusions: Preoperative abnormal HRT was significantly associated with worse short-term (in-hospital new-onset AF) and long-term outcomes (post-discharge AF recurrence/postoperative stroke) after CABG surgery. Additional studies incorporating preventive interventions depending on the preoperative HRT results might be worthwhile in this patient group. © 2014 Elsevier Ireland. Ltd
1. Introduction Atrial fibrillation (AF) is the most common arrhythmic complication after coronary artery bypass graft (CABG) surgery and is often associated with an increased risk of congestive heart failure, in-hospital stroke, prolongation of hospital stay, and rehospitalization [1–4]. Experimental and clinical studies show that impaired cardiac autonomic function contributes to the triggering and maintenance of AF [5–7]. Heart rate turbulence (HRT), a noninvasive electrocardiographic measure of cardiac autonomic function, has been introduced as a promising risk stratifier of cardiovascular death or sudden cardiac death after myocardial infarction (MI) [8–10]. However, no prospective study has described the prognostic value of HRT parameters for predicting new-onset AF in patients undergoing CABG surgery. Therefore, this prospective observation study was designed to evaluate whether the preoperative abnormal HRT could predict in-hospital ⁎ Corresponding author at: Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135710, Republic of Korea. Tel.: +82 2 3410 3414; fax: +82 2 3410 3417. E-mail address: [email protected] (J.S. Kim).
occurrence of AF after CABG surgery. We also investigated association between the preoperative abnormal HRT and recurrence of AF and AF-related embolic stroke during the follow-up period. 2. Materials and methods 2.1. Patients population. We prospectively enrolled 172 consecutive patients undergoing elective CABG surgery from May 2010 to December 2012 at the Samsung Medical Center. The main exclusion criteria were urgent/emergent surgery in which HRT examination was not feasible, pre-existing (permanent, persistent, or paroxysmal) AF rhythm or pacemaker rhythm prior to CABG, enrollment into other clinical studies, combined maze procedure, and patient's refusal. The study protocol was approved by the institutional review board of Samsung Medical Center and all subjects gave their informed consent for participation. 2.2. Definition of abnormal HRT values and measurement of HRT HRT represents a biphasic change of heart rate (HR) following premature ventricular contractions (PVCs): initial acceleration and subsequent deceleration of HR, in other words, initial decrease and subsequent increase in sinus RR interval. The two phases of HRT (the early acceleration and late deceleration of HR) are quantified by two numerical values, namely, the turbulence onset (TO) and the turbulence slope (TS), respectively [11,12]. TO was defined as the percentage change in the post-PVC RR intervals against
http://dx.doi.org/10.1016/j.ijcard.2014.04.130 0167-5273/© 2014 Elsevier Ireland. Ltd
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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the pre-PVC RR intervals. TS was defined as the maximum positive regression slope obtained over any 5 consecutive sinus RR intervals within the first 15 sinus RR intervals following the PVC. Therefore, in the normal subjects, the initial brief acceleration of HR after the PVC is represented as negative TO, and the subsequent HR deceleration is characterized by positive TS. For the present study, the values of TO N 0% and TS b 2.5 ms/RR interval were defined abnormal, respectively, as in the previous studies [11,12]. Patients were considered having normal HRT when both TO and TS were measured normal whereas those with at least one abnormal values were considered having abnormal HRT. Additionally, patients were graded into 3 groups according to the combined values of TO and TS; HRT0 group (both TO and TS were normal), HRT1 group (either TO or TS was abnormal), and HRT2 group (both TO and TS were abnormal). Ambulatory electrocardiograms were recorded 1 to 3 days prior to elective CABG surgery using an ambulatory 3-lead SEER Light Digital Holter monitor with a sampling rate of 125 samples per second (GE Healthcare Inc, Milwaukee, WI, USA), and HRT values were analyzed using a MARS 8000 Holter analyzer (GE Healthcare Inc, Milwaukee, WI, USA). For more accurate assessment of the HRT pattern, averaging responses to multiple PVCs (≥5) is needed because the HRT pattern after the PVCs can be affected by HR variability from other causes. Thus, we tried to perform Holter recordings at least 20 h prior to CABG surgery and any Holter tracing with less than 5 suitable PVCs were discarded [12]. In addition, to incorporate only suitable PVCs in the HRT assessment, a usually recommended filter settings [12,13] were adopted (Supplementary Table 1). Additionally, several time- and frequency-domain HR variability (HRV) parameters were also measured using the same system; standard deviation of all normal-to-normal RR intervals (SDNN), root mean square successive difference measures (rMSSD), low-frequency power (LF), high-frequency (HF), and LF/HF ratio.
3. Results 3.1. Characteristics of patients During the enrollment period, 172 consecutive patients underwent 24-h Holter recording prior to elective CABG surgery. Of these, 59 patients were excluded for the following reasons; 55 for insufficient number of suitable PVCs (b 5) during the Holter recordings, 3 for newly detected AF episodes during the Holter recordings prior to surgery, and 1 for premature termination of Holter recording due to aggravation of patent's symptom. Therefore, HRT measurement was possible in 113 patients and they were incorporated into the final analysis (Fig. 1). Median (IQR) age of the 113 patients was 67 (58–71) years, and the proportion of male patients was 72%. Patients with 3 vessel disease accounted for 72% of total population. Twelve patients (11%) had a history of previous coronary artery revascularization. The median (IQR) left ventricular (LV) ejection fraction (EF) and left atrial volume index (LAVi) at baseline were 58% (48–66%) and 37 (31–47) ml/m2, respectively. Off-pump CABG surgery was performed for 88 patients (78%), and 9 patients underwent combined valve surgery; 4 aortic valve replacement, 3 mitral valvuloplasty, and 5 mitral annuloplasty.
2.3. CABG surgery Pretreatment with morphine and diazepam (0.1 mg/kg) was performed for all patients prior to CABG surgery. No anti-arrhythmic agents including amiodarone, sotalol, intravenous beta-blockers, or corticosteroids were given for arrhythmia prophylaxis except potassium and magnesium supplementation, which was started in the operating room. The standard regimen of anesthesia were used for all patients. For anesthesia induction, etomidate (0.3 mg/kg), midazolam (0.1 mg/kg), and sufentanil (1–2 μg/kg) were used. Muscle relaxation was achieved with rocuronium bromide (0.6 mg/kg). For anesthesia maintenance, isoflurane, etomidate, and sufentanil were given. Midline sternotomy with standard techniques of on- or off-pump CABG surgery was carried out for all patients. The type of surgery and procedural strategies were determined by the experienced surgeon. Internal mammary artery grafts with or without saphenous vein grafts were used in all patients. Heparin (150 IU/kg) was given to obtain an activated clotting time more than 300 s. After the anastomoses were completed, protamine sulfate was administered to reverse the heparin effect. Aspirin was started within the first 24 h after surgery in all patients. Weaning from intravenous inotropic agents was guided according to standard hemodynamic criteria. Beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, amiodarone, or warfarin were used during the postoperative period when clinically indicated [14]. 2.4. Post-CABG rhythm monitoring and study outcomes The primary outcome was the incidence of new-onset postoperative AF and AF burden during the hospital stay. Monitoring the postoperative rhythm was performed continuously before discharge with the onset and termination of AF recorded on medical flow chart. Postoperative AF was defined as any documented AF N 5 min in duration or AF episodes requiring electrical cardioversion for symptomatic or hemodynamic compromise after CABG surgery. AF burden was defined as the total duration of all the AF episodes in each patients and calculated by summing up each duration of in-hospital AF episodes. The secondary outcomes were AF recurrence and postoperative stroke during the longterm follow-up. Recurrence of AF was evaluated by taking serial 12-lead ECGs (1, 3, 6, 12, and 24 months) and 24-h Holter monitor exam (12 and 24 months). If patients reported symptoms suggesting recurrence of AF at any time, 12-lead ECG and 24-h Holter monitoring were repeated. Postoperative stroke was defined as the development of a new focal neurologic deficit lasting N24 h with confirmation by computed tomographic or magnetic resonance imaging scan after the surgery. 2.5. Statistical analysis Continuous data are presented as medians with interquartile ranges (IQR) and categorical data as number with percentages. Continuous variables were compared with Mann–Whitney test and categorical variables with the Fisher's exact test. Predictors for new-onset AF after the CABG surgery were evaluated using univariate and multiple logistic regression analyses. After univariate analysis, the variables attaining a P value b 0.05 were entered into a multiple logistic regression model. Event (AF recurrence or stroke)-free survival was estimated by Kaplan–Meier analysis and the log-rank test was applied to evaluate differences between survival curves. Correlations between the grade of HRT abnormality and AF incidence or AF burden were evaluated using linear-bylinear association and Spearman's rho test for trend. All statistical analyses were performed using PASW Statistics 18 software for Microsoft (SPSS Inc., Chicago, IL, USA). All P values were two-sided and results with a P value less than 0.05 were considered statistically significant.
3.2. Patients with normal versus abnormal HRT values Preoperative median values (IQR) for TO and TS were − 0.48% (−1.43% to 0.32%) and 3.52 (1.86 to 8.11) ms/RR interval, respectively. Of the 113 patients, abnormal TO (N0%) and abnormal TS (b2.5 ms/RR interval) values were noted in 37 and 40 patients, respectively. Seventeen patients showed abnormal results in both values. Therefore, according to the definition, 60 patients were categorized as the abnormal HRT (at least one abnormal value in TO and TS) group and the remaining 53 as the normal HRT (both TO and TS normal) group (Fig. 1). Representative examples of normal and abnormal HRT were shown in Fig. 2. The baseline characteristics of patients with normal and abnormal HRT values are compared in Table 1. Patients with abnormal HRT revealed a higher prevalence of female gender, congestive heart failure, and diabetes than those with normal HRT values. Corrected QT interval, LAVi, and serum level of N-terminal prohormone brain natriuretic peptide (NT-proBNP) were measured significantly greater in the abnormal HRT compared to the normal HRT group. Several HRV variables including SDNN, LF, and LF/HF ratio were lower in the abnormal HRT group. However, there was no significant difference between the two groups in terms of previous stroke history, severity of coronary or valve disease, LV EF, and baseline medications (Tables 1 and 2). Proportions of patients who underwent off-pump CABG or combined valve surgery were not also significantly different between the two groups. 3.3. Clinical outcomes depending on the HRT values During the index hospitalization, postoperative AF episodes occurred in 39 (35%) of 113 patients. Postoperative stroke affected 3 (7.7%) of 39 patients with postoperative AF. Mean AF burden (total duration of all AF episodes) was calculated 22 ± 7 h. Electrical cardioversion was required in 5 patients and intravenous amiodarone was used in 20 patients. Postoperative AF was noted more frequently in the abnormal HRT than normal HRT group (28/60, 47% versus 11/53, 21%; P = 0.005, Fig. 3) and AF burden of the abnormal HRT group was significantly greater than that of the normal HRT group (29 ± 9 versus 7 ± 5 h, P = 0.043). Electrical cardioversion was performed only in patients with abnormal HRT values. There was a trend toward a longer hospital duration in the abnormal HRT group (11 ± 10 versus 9 ± 8 h, P = 0.199). Only 1 patient with preoperative abnormal HRT was discharged in AF, whereas the remaining 112 patients in sinus rhythm. Specific medications at discharge showed no significant difference between the two groups (Table 2).
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Fig. 1. Flow chart of the present study. AF = atrial fibrillation; CABG = coronary artery bypass graft; HRT = heart rate turbulence; PVC = premature ventricular contraction; TO = turbulence onset; TS = turbulence slope. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
During the follow-up period (12.0 ± 10.5 months) after discharge, 9 (8%) of the 113 patients experienced secondary outcomes: 7 patients had recurrent AF requiring standard treatment (anticoagulation, rate, or rhythm management) and additional strokes were observed in 2 patients. The secondary outcomes developed only in patients who had shown postoperative AF during the index hospitalization (9/39, 23% versus 0/74, 0%; P b 0.001). Regarding the secondary outcomes as well, the abnormal HRT group showed a worse prognosis versus the normal HRT group (Fig. 4).
3.4. Independent predictors associated with adverse outcomes. To assess the independent predictors associated with postoperative AF, multivariate logistic regression models were constructed with risk variables attaining P values b 0.05 on univariate analysis (Table 3). Heart failure history, LV EF b 50%, LAVi ≥ 40 ml/m2, and abnormal HRT were significantly associated with the development of postoperative AF on univariate analysis. Among these parameters, abnormal HRT
Fig. 2. Representative examples of normal and abnormal HRT. SR = sinus rhythm; other abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Table 1 Comparison of baseline characteristics.
Demographics Age, years Male gender, n (%) Congestive heart failure, n (%) Hypertension, n (%) Diabetes, n (%) Chronic kidney disease, n (%) Previous stroke or TIA, n (%) Previous MI, n (%) Previous PCI or CABG, n (%) 3 vessel disease, n (%) Electrocardiographic or 24-h Holter data Average heart rate, bpm QRS duration, ms QTc interval, ms Premature ventricular contraction, n SDNN rMSSD Low-frequency power High-frequency power Low-frequency/high-frequency ratio Echocardiographic parameters LV ejection fraction,% Left atrial volume index, ml/m2 Moderate to severe VHD, n (%) Laboratory values hs-CRP, mg/dl NT-proBNP, pg/ml Operations Off-pump CABG, n (%) Combined valve surgery, n (%)
Normal HRT (n = 53)
Abnormal HRT (n = 60)
P value
65 (56–71) 43 (81) 1 (2) 42 (79) 18 (34) 8 (15) 5 (9) 3 (6) 5 (9) 39 (74)
68 (63–72) 38 (63) 11 (18) 42 (70) 39 (65) 18 (30) 9 (15) 1 (2) 7 (12) 42 (71)
0.072 0.039 0.005 0.288 0.001 0.075 0.407 0.340 0.767 0.835
69 (65–74) 96 (90–105) 418 (409–438) 64 (19–151) 89 (71–100) 20 (15–24) 12.6 (9.9–15.9) 7.9 (6.5–9.6) 1.6 (1.3–2.0)
72 (65–78) 92 (86–100) 438 (420–534) 71 (21–387) 81 (64–93) 20 (15–24) 10.7 (6.8–13.5) 7.6 (5.2–11.1) 1.3 (1.0–1.7)
0.251 0.071 0.004 0.173 0.032 0.892 0.005 0.366 0.001
59 (50–67) 35 (29–43) 3 (6)
58 (44–66) 40 (34–53) 5 (8)
0.146 0.002 0.721
0.12 (0.04–0.41) 1150 (400–4125)
0.26 (0.07–0.86) 2550 (675–8600)
0.055 0.004
41 (77) 3 (6)
47 (78) 6 (10)
1.000 0.498
CABG = coronary artery bypass graft surgery; hs-CRP = high-sensitivity C-reactive protein; HRT = heart rate turbulence; LV = left ventricular; MI = myocardial infarction; NT-proBNP = N-terminal prohormone brain natriuretic peptide; PCI = percutaneous coronary intervention; QTc = corrected QT; rMSSD = root mean square successive difference measures; SDNN = standard deviation of normal-to-normal beat intervals; TIA = transient ischemic attack; VHD = valvular heart disease.
and LAVi ≥ 40 ml/m2 were identified as independent predictors for the development of postoperative AF. 3.5. Correlation between the grade of HRT abnormality and clinical outcomes
AF burden (r = 0.310, P = 0.001) and the duration of hospital stay (r = 0.184, P = 0.050). In a similar way, regarding the secondary endpoints, the HRT2 group showed the worst prognosis whereas the HRT0 group the most benign course (Fig. 5B). 4. Discussion
To assess the clinical outcomes depending on the grade of HRT abnormality, we divided the 113 patients into 3 groups according to the combined values of TO and TS; HRT0 group (n = 53, both TO and TS were normal), HRT1 group (n = 43, either TO or TS was abnormal), and HRT2 group (n = 17, both TO and TS were abnormal). The incidence of postoperative AF gradually increased as the number of abnormal HRT values increased from 0 to 2 (P for trend = 0.001, Fig. 5A). The number of abnormal HRT values was also positively correlated with postoperative
4.1. New findings The present study is the first to show a significant association between the preoperative HRT abnormality and the increased risk of
Table 2 Comparison of medications.
Baseline Aspirin, n (%) Clopidogrel, n (%) ACEI or ARB, n (%) Statin, n (%) Beta-blocker, n (%) At discharge Aspirin, n (%) Clopidogrel, n (%) Warfarin, n (%) ACEI or ARB, n (%) Statin, n (%) Beta-blocker, n (%) Amiodarone, n (%)
Normal HRT (n = 53)
Abnormal HRT (n = 60)
P value
34 (64) 9 (17) 17 (32) 27 (51) 17 (32)
36 (60) 12 (20) 11 (18) 26 (43) 21 (35)
0.701 0.810 0.126 0.454 0.842
53 (100) 31 (59) 3 (6) 11 (36) 42 (79) 48 (91) 4 (8)
58 (97) 27 (45) 7 (12) 8 (42) 49 (82) 51 (85) 5 (8)
0.497 0.188 0.331 0.566 0.814 0.407 1.000
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HRT = heart rate turbulence.
Fig. 3. In-hospital outcomes depending on preoperative HRT values. *AF burden was defined as the total duration of all the AF episodes in each patient. Abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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Fig. 4. Kaplan–Meier event-free curves for the secondary outcomes (AF recurrence and postoperative stroke) based on preoperative HRT values. Abbreviations as in Fig. 1. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
postoperative new-onset AF in patients undergoing CABG surgery. Although there have been many studies dealing with clinical implications of HRT, most of the previous evaluations primarily focused on the risk of cardiac death, ventricular tachyarrhythmia, and sudden cardiac death after acute MI [7–9]. One retrospective data suggested that HRT-based autonomic dysfunction was associated with the development of postoperative AF in 100 patients who underwent cardiac valve or CABG surgery [15]; however, long-term outcomes were not presented. In contrast, our study provided prospectively short- and long-term prognostic value of HRT measurement; in our results, approximately 50% of patients undergoing CABG surgery had preoperative autonomic dysfunction suggested by HRT analysis and patients with abnormal HRT values showed more than two times increased risk of developing postoperative AF. Abnormal HRT was also independently associated with postoperative new-onset AF even after adjusted for relevant clinical and echocardiographic parameters. During the follow-up period as well, AF recurrence and stroke developed more frequently in patients with preoperative abnormal HRT than those with normal HRT. In addition, the short- and long-term clinical outcomes became gradually worse as the grade of HRT abnormality increased, interestingly, which findings are coherent
Fig. 5. Clinical outcomes based on the grade of HRT abnormality. Patients were divided into 3 groups based on the combined values of TO and TS; HRT0 group (both TO and TS were normal), HRT1 group (either TO or TS was abnormal), and HRT2 group (both TO and TS were abnormal). (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Table 3 Predictors for postoperative AF. Characteristics
Age ≥ 65 years, n (%) Male gender, n (%) CHF, n (%) Diabetes, n (%) QTc interval, ms LV EF b 50%, n (%) LAVi ≥ 40 ml/m2, n (%) hs-CRP, mg/dl NT-proBNP, pg/ml Beta-blocker, n (%) Statin, n (%) OPCABG, n (%) TO, % TS, ms/RR Abnormal HRT, n (%)
Non-PAF
PAF
(n = 74)
(n = 39)
P value
Univariate analysis
43 (58) 53 (72) 4 (5) 36 (49) 421 (409–453) 18 (25) 19 (26) 0.11 (0.04–0.45) 139 (71–443) 24 (32) 35 (47) 61 (82) −0.97 (−2.02 to −0.02) 3.9 (2.2–10.2) 32 (43)
26 (67) 28 (72) 8 (21) 21 (54) 436 (423–449) 16 (43) 25 (68) 0.34 (0.12–1.18) 795 (71–1799) 14 (36) 18 (46) 27 (69) −0.01 (−0.49 to 0.68) 2.4 (1.1–4.2) 28 (72)
0.422 1.000 0.022 0.693 0.052 0.053 b0.001 0.003 0.003 0.843 1.000 0.152 b0.001 0.003 0.005
Multivariate analysis
Odds ratio (95% CI)
P value
1.01 (0.43–2.39) 4.45 (1.25–15.9) 1.23 (0.57–2.68) 1.01 (0.99–1.02) 2.33 (1.01–5.40) 6.03 (2.54–14.3) 0.99 (0.98–1.01) 1.00 (1.00–1.00)
0.984 0.021 0.600 0.213 0.049 b0.001 0.613 0.157
1.23 (1.01–1.50) 0.897 (0.81–0.99) 3.34 (1.45–7.70)
0.045 0.029 0.005
Odds ratio (95% CI)
P value
1.77 (0.37–8.46)
0.475
1.32 (0.45–3.87) 4.58 (1.85–11.4)
0.611 0.001
2.64 (1.03–6.80)
0.044
CHF = congestive heart failure; EF = ejection fraction; OPCABG = off-pump CABG; TO = turbulence onset; TS = turbulence slope and other abbreviations as in Table 1.
Please cite this article as: Park S-J, et al, Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.130
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S.-J. Park et al. / International Journal of Cardiology xxx (2014) xxx–xxx
with several previous studies reporting the worst prognosis in patients with both abnormal results in TO and TS [8,16]. 4.2. Abnormal HRT and the risk of postoperative AF Although the exact physiologic mechanisms of the PVC-induced HRT are not fully elucidated, baroreflex-medicated cardiac autonomic function is considered to play a central role [12]. Transient BP reduction caused by ineffective PVCs activates aortic and carotid baroreceptors, which induces vagal inhibition leading to initial HR acceleration. However, 10 to 20 beats later, the initial HR acceleration is followed by a subsequent HR deceleration to the pre-PVC level by vagal reactivation. Therefore, abnormal HRT values (TO N 0% and/or TS b 2.5 ms/RR) represent cardiac autonomic dysfunction; abnormally elevated vagal tone might blunt the early HR increase resulting in a positive TO value (N 0%), whereas abnormally enhanced sympathetic tone might attenuate the late HR decrease leading to a lower TS value (b2.5 ms/RR). Then this cardiac autonomic dysfunction/imbalance is known to contribute to the triggering and maintenance of postoperative or post-MI AF [5,17,18]; vagal activation shortens the atrial refractory period making AF wavelengths smaller and depolarized atrial tissue recover rapidly. Therefore, multiple AF wave fronts can find remaining excitable atrial tissue on and on. Enhanced sympathetic stimulation can increase automaticity of atrial ectopic focus [19]. In post-MI patients, disturbances in the cardiac autonomic regulation suggested by abnormal HRV or HRT parameters were associated with increased risk of new-onset AF independently of conventional clinical risk variables [18]. Autonomic modulation using botulinum toxin (for vagal tone), beta blocking agents (for sympathetic tone), and ablation of ganglionic plexi (for vagal/sympathetic tone) has been suggested as an effective method to reduce postoperative AF in many preclinical experiments and clinical trials [20–22]. On the other hand, impaired cardiac autonomic function may be a marker of more severe cardiovascular dysfunction, which itself could make patients more susceptible to the postoperative AF; HRT values are shown to be affected by LV systolic dysfunction and advanced age [12]. Indeed in our data, LV EF was lower and NT-proBNP level was significantly higher in patients with abnormal HRT versus those with normal HRT. 4.3. Clinical implications Pretreatment with several medications such as beta-blockers, statin, ACEI, and amiodarone has been effective for reducing the postoperative AF in patients undergoing CABG surgery [21,23–25]. Then most of the patients undergoing CABG surgery often have indications for these medications due to other conditions including hypertension, hypercholesterolemia, and diabetes. However, amiodarone use is not always straightforward as the other agents due to its potential side effects [25]. Therefore, stratification of patients at higher risk for postoperative AF using preoperative HRT measurement might be useful in deciding whether to perform an amiodarone prophylaxis. There are several other methods by which cardiac autonomic dysfunction can be evaluated such as HRV and baroreflex sensitivity using phenylnephrine infusion [26]. However, phenylnephrine, an alpha-adrenergic agent, might also aggravate myocardial ischemia by elevating blood pressure especially in patients with unstable angina. In contrast, ambulatory ECG-based HRT measurement is easy to perform and feasible even in patients who cannot tolerate exercise or vasoactive drug challenge (e.g., phenylnephrine). Additionally, invasive procedure such as intravenous cannulation is not required. HRV measurement could be limited by frequent premature atrial/ventricular contractions. However, the occurrence of premature beats is a precondition for HRT measurement, Therefore, both HRV and HRT, as good markers of autonomic dysregulations, could be measured simultaneously using a 24-h Holter recordings and used in a complimentary way to improve a discriminatory power for post-CABG AF.
4.4. Study limitations The present study has the limitations inherent to the way HRT values are measured; HRT evaluation is not possible in patients without PVCs. It cannot be measured in patients with persistent/permanent AF or pacemaker rhythm as well. In addition, patients who require emergent/ urgent CABG surgeries may be ineligible. The incidence of postoperative AF in our data was higher than those from other reports [23,27], therefore, the same results might not always be found in other study populations and our results need to be interpreted with caution. The higher incidence of AF may be related, at least partly, to the fact that 30% of our patients underwent on-pump CABG or combined valve surgery that are well known to increase the rate of post-CABG AF. Efficacy of preventive interventions depending on the HRT abnormality was not evaluated in our study. Therefore, more prospective studies with preventive approaches are needed to validate our findings more definitely. 5. Conclusion Preoperative abnormal HRT was identified as an independent predictor of postoperative in-hospital new-onset AF in patients undergoing CABG surgery. It was also significantly associated as worse long-term outcomes; AF recurrence and postoperative stroke. These short- and long-term risks were gradually elevated as the grade of HRT abnormality increased. Additional prospective studies incorporating preventive interventions depending on the preoperative HRT results may be worthwhile to show the clinical implication of the HRT measurement more definitely in this patient group. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.04.130. Acknowledgements The authors are grateful for the invaluable contributions from the following specialists at the Samsung Medical Center: Soo-Young Cho, RN. and Soo-Youn Kim, Ms. for data collection. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–73. [2] Lahtinen J, Biancari F, Salmela E, et al. Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:1241–4. [3] Mariscalco G, Klersy C, Zanobini M, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation 2008;118:1612–28. [4] Song SW, Sul SY, Lee HJ, Yoo KJ. Comparison of the radial artery and saphenous vein as composite grafts in off-pump coronary artery bypass grafting in elderly patients: a randomized controlled trial. Korean Circ J 2012;42:107–12. [5] Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264–74. [6] Bauernschmitt R, Malberg H, Wessel N, et al. Autonomic control in patients experiencing atrial fibrillation after cardiac surgery. Pacing Clin Electrophysiol 2007;30:77–84. [7] Dimmer C, Tavernier R, Gjorgov N, Van Nooten G, Clement DL, Jordaens L. Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 1998;82:22–5. [8] Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999;353:1390–6. [9] Ghuran A, Reid F, La Rovere MT, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (the Autonomic Tone and Reflexes After Myocardial Infarction substudy). Am J Cardiol 2002;89:184–90. [10] Mäkikallio TH, Barthel P, Schneider R, et al. Prediction of sudden cardiac death after acute myocardial infarction: role of Holter monitoring in the modern treatment era. Eur Heart J 2005;26:762–9. [11] Hoshida K, Miwa Y, Miyakoshi M, et al. Simultaneous assessment of T-wave alternans and heart rate turbulence on Holter electrocardiograms as predictors for serious cardiac events in patients after myocardial infarction. Circ J 2013;77:432–8.
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