Heart rate variability decreased by coronary artery surgery has no prognostic value

Short title: Low HRV and survival after CABG

Authors: Goran Milicevic, Ljubica Forta, Marcel Majseca and Vinko Bakula.

Affiliations of the authors: General Hospital Sveti Duh, Zagreb, and aHospital for Medical Rehabilitation, Krapinske Toplice, Croatia.

Previous presentations: The work was presented in a part at the 3rd International Congress of the Mediterranean Society of Pacing and Electrophysiology, Lisbon 2003.

Support: The study was supported from the Project 0219163 of the Ministry of Science and Technology of the Republic of Croatia (Diagnosis and Therapy of Decreased Heart Rate Variability).

Potential conflict of interest: NONE

Correspondence and reprints:

Asst. Prof. Goran Milicevic,

Division of Cardiology, Clinical Hospital Sveti Duh,

Sveti Duh 64, HR-10000 Zagreb, Croatia

fax: +385 13712308,

ph. +385 913712213,

e-mail.

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Abstract

Background: Decreased heart rate variability (HRV) may predict cardiac death after myocardial infarction (MI). Coronary artery bypass grafting (CABG) strongly decreases HRV, but improves survival. The aim of the study was to determine the prognostic value of HRV decreased by coronary surgery.

Design and Methods: Four-year follow-up was performed in 175 consecutive patients with HRV decreased by CABG (51) or MI (124). Mortality and secondary events rate were analyzed. Decreased HRV, defined by the standard deviation of mean RR interval (SDNN) < 100 ms, was detected by a routine 24-hour Holter ECG at admission to stationary rehabilitation 3 weeks to 3 months after acute MI or CABG. Two groups did not differ except by age; CABG patients were younger (56 vs 64 years, p<0.01), but this did not influence differences in survival (NS).

Results: HRV was lower among CABG patients than among MI patients (SDNN = 66±20 ms vs 77±14 ms; p<0.001), but cumulative survival and event-free survival were much better in the CABG group than in the MI group. During a 46±20 months follow-up, there were 10% new events in the CABG and 43% in the MI group (p<0.001). Mortality was 8% in the CABG and 33% in the MI group (log-rank=3.6; p<0.001). Unlike in the MI group, HRV was not different between survivors and non-survivors in the CABG group.

Conclusions: In contrast to the strong prognostic potential of HRV in patients with MI, decreased HRV has no prognostic significance in patients who have undergone CABG surgery.

Abstract wordcount: 248

Key words: prognosis, survival, heart rate variability, coronary artery bypass grafting, myocardial infarction


Introduction

Decreased heart rate variability (HRV) has been found to be an important predictor of cardiac death in patients with myocardial infarction [1]. Measurement of HRV had prognostic value in unselected older population [2] and attempts were made to involve HRV in a routine clinical practice [3, 4]. However, it seems that HRV may not be useful in all coronary disease settings [5, 6].

Coronary artery bypass grafting improves survival [7], but simultaneously decreases HRV [8-11] even more than myocardial infarction does [12]. This may seem contradictory to someone who uses low HRV as a prognostic marker of an increased risk of cardiac death. Clinical practice shows that cardiac surgery patients with extremely decreased HRV often have an excellent outcome. Stein et al. [5] have found no prognostic significance for HRV decreased by cardiac surgery in a retrospective study, but there is very little prospective data.

Therefore, the aim of this study was to define the prognostic significance of decreased HRV in cardiac bypass surgery patients. For that purpose, we analysed the survival of patients with HRV decreased in association with coronary artery bypass grafting and compared it with the survival of patients whose HRV was decreased in association with myocardial infarction.

Methods

Patients

Survival was prospectively analysed in 175 consecutive stationary cardiac rehabilitation patients who were in sinus rhythm and with no sinus node disease or second or third-degree atrioventricular block, but whose routine made 24-hour Holter electrocardiogram showed decreased HRV. They had suffered myocardial infarction (MI; 124 patients) or undergone coronary artery bypass grafting (CABG; 51 patients) 3 weeks to 3 months before. Electrocardiogram and enzyme testing verified the diagnosis of MI. Cardiac surgery was performed by the use of an extracorporal circulation machine. All CABG patients received 3 or more bypass grafts. Patients with perioperative infarction and those with urgent revascularization following myocardial infarction were not included, nor were not those older than 79 years or those with diseases limiting survival or affecting HRV (cancer, stroke, insulin-dependent diabetes, thyroid disease).

Survival of CABG patients was compared with that of MI patients because of each group had the same underlying (coronary artery) disease. There was no significant difference (NS) between the myocardial infarction and CABG groups for gender (71% male), incidence of hypertension (24%), diabetes (19%), left ventricular systolic dysfunction (34%) defined by ejection fraction lower than 40%, and time elapsed from their MI (1.6±0.8 months) or CABG (1.5±0.9 months). There were no differences in the use of medication (beta adrenergic blockers, digoxine, amiodaron, sotalol, propafenon, mexiletine, calcium channels antagonists, angiotensin-converting enzyme inhibitors, nitrates and diuretics) either. The only significant difference recorded was age; CABG patients were younger (56±11 vs 64±9 years, p<0.01).

Follow-up

As approved by the Hospital Ethics Committee, a questionnaire on the present health status was mailed to patients. If there was no response, the family physician was contacted. This study focused on combined cardiovascular and cerebrovascular mortality as the primary endpoint and on both fatal and nonfatal events (myocardial infarction, unstable angina, stroke and transient ischemic attacks) as the secondary endpoint. Fife of 129 MI patients enrolled in the study were excluded because of a non-cardiovascular cause of death (cancer). Those who underwent cardiac revascularization procedures (coronary angioplasty or bypass surgery) during the follow-up were considered alive at the date of intervention and excluded from further analysis.

Measurements

HRV was calculated from 24-hour Holter electrocardiogram, by a commercial system (Oxford Instruments). R-R intervals that included ectopic beats were excluded and extrapolated by linear interpolation. Spectral analysis was computed using fast Fourier transformation. Ten-minute epochs were repeatedly transformed and averaged throughout the 24-hour period. Details were published elsewhere [4]. Standard deviation of mean RR interval (SDNN) was used as a representative of overall HRV. The cut-off between the normal and moderately diminished HRV was defined arbitrarily by the value of SDNN lower then 100 ms [1]. Most of the variables proposed by the Task Force on the Heart Rate Variability [3] were analyzed. Left ventricular ejection fraction was determined by a Simpson rule, from apical four- and two-chamber view.

Statistics

Differences in patient characteristics were analysed by Fisher exact test for categorical variables and by Student’s t-test for continuous variables. Most of the HRV variables analysed best fit a logarithmic distribution [4], so median values are given for comparison between MI and CABG groups in Table 1. Median values of logarithmically transformed variables were compared by the Mann-Whitney U-test. Except in Table 1, all possible differences in the SDNN were analysed by t-test, because SDNN was normally distributed [4].

Significance of differences in the rate of events or death between the two groups was verified by Fisher exact tests. Time to death and time to predefined cardiovascular events was analysed by the Kaplan-Meier method and compared with the log-rank test. The effects of sex, age, time elapsed from MI or CABG, concomitant diseases, left ventricular ejection fraction and medication on difference in the survival was analyzed by proportional hazard (Cox) regression. SPSS for Windows, version 7.5 was used.

Results

Overall HRV was lower among CABG patients than among MI patients (SDNN = 66±20 ms vs 77±14 ms; p<0.001), independent of positive or negative history of MI prior to coronary artery surgery (SDNN = 68±21 ms vs 64±21 ms; NS). In contrast to overall HRV, the values of other HRV variables (rMSSD, pNN50, LF, HF, LF/HF ratio) did not differ between the two groups (Table 1).

During the follow-up period (46±20 months, range 0.03 to 77), 45 patients died and 13 survived secondary cardiovascular or cerebrovascular event. Seventeen patients, all from the MI group, underwent revascularisation procedures and sustained no further secondary events. Cumulative survival and cumulative event-free survival were much better in the CABG group than in the MI group. New events occurred in five (10%) CABG patients and in 53 (43%) MI patients (p<0.001). Four (8%) CABG patients and 41 (33%) MI patients died (p<0.001). Kaplan-Meier curves depicting difference in cumulative survival are shown in Figure 1, and the log-rank test confirmed the same difference (p<0.001) for the survival and for the event-free survival.

The paradoxical finding of better survival in the group with worse HRV would indicate that HRV has no prognostic value in CABG group or has no prognostic value at all. The latter is not true because survival was strongly related to HRV in MI group. Deceased MI patients had lower SDNN than those who survived the follow-up period (68±15 ms vs 82±12 ms; p<0.001). The same difference was found for the event-free survival in the MI group (69±14 ms vs 83±12 ms; p<0.001). That was not the case in the CABG group. The difference in HRV between survivors (SDNN 67±21 ms) and non-survivors (SDNN 59±20 ms) did not reach statistical significance among the CABG patients. The same difference was found for the event-free survival (SDNN was 67±20 ms in survivors and 58±22 ms in non-survivors; difference NS), confirming that HRV has no prognostic value only in CABG patients.

Beside HRV, the two groups also differed according to age, however, the age difference did not influence differences in survival (c2 value was 0.24 for survival and 1.18 for event-free survival; NS both).

Discussion

This study clearly documents that the usual association between depressed HRV and increased mortality does not exist in coronary artery disease patients who have undergone bypass surgery. The seemingly contradictory findings of a simultaneous decrease in HRV and improvement in survival by CABG indicate that the low HRV is not an invariable predictor of an adverse outcome. Conversely, the prognostic value of a decreased HRV was confirmed once more for MI patients.

Our results are consistent with data reported retrospectively from the CAST trial by Stein and colleagues [5] where post-CABG patients had markedly decreased HRV in conjunction with improved short-term survival. They also concluded that "recognition of this is necessary to prevent misclassification of risk". Similar opinion on the value of decreased HRV as a prognostic marker in the absence of myocardial infarction can be found elsewhere in the literature [6], but the explanation for this opinion was not given.

A non-lethal decrease of HRV in CABG patients can be explained by the increase of perioperative sympathetic activity and by a mechanism of autonomic denervation different from that accompanying heart infarction, i.e., myocardial necrosis. The decrease in HRV following CABG is related to increased sympathetic activity and to perioperative procedures [9], so our findings are actually consistent with what might be expected. It seems that the heart, denervated by a surgeon knife and simultaneously stimulated by revascularisation, has a great potential of autonomic reinnervation. There is evidence that HRV decreased in such a manner can recover completely over a period of time [10]. Thus, it appears that a non-pathologic, postoperatively decreased HRV has no importance for the routine clinical work and postoperative prognosis during, at least, the first months following cardiac surgery.

An incidental finding of the study was that there were no differences in HRV indices which reflect specific components of overall autonomic modulation of heart rate (rMSSD, pNN50, LF, HF) between the CABG and MI groups. That could be the consequence of a smaller perioperative decrease in these segments than in overall HRV [10]. The lack of difference in HF, pNN50 and rMSSD could equally be due to the fact that among cardiac patients there is a high prevalence of non-respiratory sinus arrhythmia which exaggerates HRV in some patients and does not reflect cardiac autonomic modulation. However, it seems that central frequency of the HRV spectrum shifts leftward in association with progression in ischemic heart disease [13], and probably, because of that, long-term measures of sympathovagal balance do not reflect clinical finding in cardiac patients with low overall HRV [14]. We hope that our ongoing study of perioperative changes of HRV will shed more light upon this discrepancy in the changes of HRV elements.

Although not the primary focus of this study, the mortality rate in the MI group (30% in 3 years) seems to be very high. That fact does not surprise us because in our country myocardial infarction patients who undergo stationary cardiac rehabilitation are generally at higher risk, and because only those with low HRV were included. A similar mortality rate has been found in other myocardial infarction patients with decreased HRV [1].

The limitation of this study is that groups selected by low HRV do not represent all patients with MI or CABG, but our intention was just to analyse predictive value of decreased HRV in CABG patients, not in a general cardiac population. From a methodological stand this may not be the optimal approach. It remains possible that low HRV after CABG would have a predictive value when compared to patients with normal or high HRV after CABG, but survival in CABG patients with low HRV was too good to compare it with that in patients with normal HRV. Finally, it would be interesting to define predictive value of decreased HRV in diabetic patients because Stein and co-workers [5] found in the CAST sample low predictive value of HRV not only for CABG, but for diabetic patients as well. Unfortunately, our sample was too small to test this hypothesis.

The study protocol covered cardiovascular events, but the mode of cardiac death was not analysed, what might be considered as a limitation of the study as well. The reason for that was the small number of deceased patients (only four) in the CABG group. Due to technical limitations, we obtain no measurements of baroreflex sensitivity [15, 16] or of other indexes of autonomic nervous system activity that have been associated with increased mortality risk [17]. It is possible that measurement of these parameters would have added insights into the previously mentioned difference in the decrease of overall HRV compared with other HRV parameters that reflect activity of different components of the autonomic nervous system.