CLINICAL CHARACTERISTICS

The characteristics of the study population are summarised in table 1. There were no significant differences in clinical profiles and echocardiographic findings between the two groups. Tables 2 summarises the clinical, Holter monitoring, and angiographic characteristics. Overall, 56 episodes of ischaemic ST segment elevation were observed while recording 24 hour Holter ECGs. We excluded 18 ischaemic episodes in which other attacks were observed within one hour before or after the ischaemic episode. We therefore analysed and examined 38 episodes (average of 3.2 (0.8) episodes/patient in the MA group). The ischaemic episodes continued for 3.6 (1.1) minutes (range 2.0 to 5.0 minutes) and the ST segment elevation was 3.3 (1.0) mm (range 2.0 to 5.0 mm).

COMPARISON OF HEART RATE VARIABILITY INDICES

Table 3 shows the serial data of heart rate variability indices in the SA and MA groups. The data are shown in fig 1.

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Figure 1

Graphs showing RR interval (A), LF (B), HF (C) and LF/HF ratio (D) in the single attack (SA) group (○) and the multiple attack (MA) group (•) from 40 minutes before an attack to 30 minutes after an attack. For clarity, SD bars are not shown. Baseline = averaged value during the 40 to 30 minute period before an attack. The averaged RR interval in the MA group was significantly higher than in the SA group (p < 0.01). In both groups, HF significantly decreased compared with baseline at two minutes before an attack, while LF and LF/HF were significantly reduced compared with baseline at three minutes before an attack. For LF and LF/HF, the MA group showed significantly lower values than the SA group before and after the attack (p < 0.01, respectively). *p < 0.05 v MA group; †p < 0.01 v MA group; §p < 0.05 v baseline; ¶p < 0.01 v baseline. LF, low frequency component (0.04–0.15 Hz); HF, high frequency component (0.15–0.40 Hz).

Figure 1A shows the changes in RR interval in the two groups. The averaged RR interval (averaged interval from 40 minutes before to 30 minutes after an attack) in the MA group was significantly longer than in the SA group (1043 (83) v 901 (117) ms, p < 0.01). There was no significant variation until 0.5 minutes before an attack in the MA group, and until one minute before an attack in the SA group. However, the RR interval in the MA group was decreased at the time of the attack compared with baseline (p < 0.01), and then gradually returned to baseline. In the SA group, the RR interval was reduced at one minute before an attack compared with baseline (p < 0.01), and then returned to the baseline immediately after the attack.

Panels B, C, and D in fig 1 show, respectively, the changes in LF, HF, and LF/HF ratio in the two groups. The averaged LF (averaged value from 40 minutes before to 30 minutes after an attack) was higher in the SA group than in the MA group, at 6.98 (0.55) v6.14 (0.86) ms², p < 0.01. The LF component in both groups decreased at three minutes before the onset of ischaemia compared with baseline (p < 0.01), and then significantly increased at the onset of ischaemia (p < 0.01). HF levels were similar in both groups during the 40 minute to 0.5 minute period before an attack and in the 1.5 to 30 minute period after an attack. At the onset of an attack, the HF component in the SA group was higher than in the MA group (p < 0.01). In both groups, the HF component was significantly reduced at two minutes preceding the onset of ischaemia compared with baseline (p < 0.01), and then increased at the onset of ischaemia (p < 0.01). The averaged LF/HF ratio (averaged from 40 minutes before to 30 minutes after an attack) in the SA group was higher than in the MA group, at 1.52 (0.25) v 0.73 (0.32), p < 0.01. The LF/HF ratio in both groups fell at three minutes before the onset of ischaemia compared with baseline (p < 0.01), and then became significantly increased at two minutes before ischaemia (p < 0.01).

SUBGROUP ANALYSIS

Table 4 shows the serial data of heart rate variability indices in 13 patients with right coronary spasm. The data are shown in fig 2.

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Figure 2

Graphs showing RR interval (E), LF (F), HF (G), and LF/HF ratio (H) in the single attack (SA) group (○) and the multiple attack (MA) group (•) with ST segment elevation in the modified lead II of the Holter ECG from 40 minutes before an attack to 30 minutes after an attack. For clarity, SD bars are not shown. Baseline = averaged value during the 40 to 30 minute period before an attack. The results are similar to those of fig 1. *p < 0.05 v MA group; †p < 0.01 v MA group; §p < 0.05 v baseline; ¶p < 0.01 v baseline. LF, low frequency component (0.04–0.15 Hz); HF, high frequency component (0.15–0.40 Hz).

In these figures, the findings in the subgroups were similar to the results for all subjects.

ASSESSMENT OF HEART RATE VARIABILITY BY SPECTRAL ANALYSIS

High frequency power represents the vagal function of heart rate caused by the respiratory cycle and the depth of respiration.18 ,19 Low frequency power reflects the adjustment of both vagal and sympathetic activities.24 ,25Several previous reports have used the LF/HF ratio to measure the sympathovagal balance.9 ,18 The LF/HF ratio may not only provide insight into autonomic balance, but also an estimate of sympathetic activity, providing an estimate of vagal tone is available. Time based frequency domain analysis of heart rate variability has great promise for studying the dynamics of the autonomic nervous system.26 In this study, the HF showed comparable values between the two groups before and after ischaemic episodes at rest in the night periods. We therefore used the LF/HF ratio to assess sympathetic activity.

A previous study reported that the HF component increased during the 10 minute period before ischaemic episodes of nocturnal variant angina, whereas the LF component increased during the five minute period before such episodes11; another study reported that although the HF components transiently and significantly decreased at two minutes before an attack, the LF/HF ratio did not show any significant change.12 The special report inCirculation 27 recommends two minute intervals to study the LF component. Thus almost all previous studies have been performed using a minimum interval of two minutes. However, important data may be lost during those two minutes, because autonomic nervous activity changes markedly before and after the onset of ischaemic episodes. In these previous studies, the spectral technique was based on the FFT. However, the FFT has its own drawbacks, such as poor resolution owing to the effect of window functions, and unrealistic assumptions about extending the data. Furthermore, the FFT is insufficient to estimate the precise power spectral density from short time series data.

The present analysis was carried out using the MemCalc method.13-16 This method is a new technique for time series analysis, which is a combination of the MEM for spectral analysis and the non-linear LSM for fitting the analysis in the time domain. This new method enabled us to achieve a reliable analysis of the low frequency component (LF, 0.15–0.40 Hz) on a minimum interval of 30 seconds. In our data, the HF showed a significant decrease transiently at two minutes before an attack, and the LF/HF ratio significantly fell at three minutes before an attack. This findings imply that the decrease in vagal activity is preceded by a reduction in sympathetic activity. Furthermore, the LF/HF ratio in the MA group was always low compared with the SA group. This suggests that a reduction in sympathetic nerve tone before and after the attacks is involved in setting the scene for the recurrent ischaemic episodes. Our results differ from those of previous studies11 ,12 showing that an activation of the sympathetic system or a deactivation of the parasympathetic system appeared to play a role in triggering transient myocardial ischaemia caused by coronary spasm. However, spectral analysis was performed for longer periods (two minutes) using the FFT in those previous studies.

PATHOGENESIS OF CORONARY ARTERY SPASM

After coronary artery spasm became a proven cause of variant angina, various pathogenic hypotheses were suggested to explain the origin of this syndrome. However, the fundamental mechanism of coronary spasm has not yet been clearly shown.28 We previously reported that there was regional myocardial sympathetic dysfunction in patients with coronary vasospasm.7 Some studies have suggested that activation of sympathetic activity could be the main cause of coronary spasm,29-31 but others have denied this hypothesis.32 ,33 On the other hand, because most patients tend to have anginal attacks at rest during the night,34 ,35 or because of the possibility that cholinergic agents might induce coronary spasm,5 ,36 ,37it has been suggested that vagal activity may play a significant role in coronary spasm. However, the concentration of drugs necessary to induce coronary spasm was greater than that generated physiologically in the coronary arteries. Furthermore, angina at night is considered to occur usually during REM sleep,38 and some recent studies have reported that sympathetic activity plays a role in triggering ischaemic attacks during REM sleep.39 ,40 In the present study, it was difficult to determine sleep level because we did not use electroencephalography or polysomnography. However, the fact that most attacks occurred at night and that before an attack significant variations of LF/HF ratio were observed, preceding the rapid HF variation in our data, suggests that a change in sympathetic activity triggered the onset of coronary spasm.

EXAMINATION OF THE SUBGROUPS

Several studies have reported changes in heart rate variability according to whether the left or the right coronary artery was occluded. In one study, heart rate variability analysis during balloon coronary angioplasty was reported in a group with occlusion of the right coronary artery compared with a group with occlusion of the left coronary artery; some cases showed increased heart rate variability and others showed decreased variability, but no significant difference was observed between the two groups.41 In another study it was reported that among cases with acute myocardial infarction, heart rate variability was lower in those with anterior infarction than in those with posterior infarction.42

To assess whether heart rate variability indices are affected by the site of coronary spasm, we examined the subgroup subjects in the same way. The results for the subgroups were similar to those for all subjects combined, implying that the heart rate variability indices in the present study were not affected by the site of coronary spasm.

STUDY LIMITATIONS

First, the LF/HF ratio will not provide an accurate measure of sympathetic tone. Vagal activity is the major contributor to the HF component,18 ,19 but there is disagreement with respect to the LF component. It has been suggested8 that LF, when expressed in normalised units, is a quantitative marker of sympathetic modulation; alternatively it has been suggested that LF reflects both sympathetic activity and vagal activity.9 Consequently, the LF/HF ratio is considered by some investigators21-23to reflect sympathetic modulation. We therefore used the LF/HF ratio as a better indicator of sympathetic activity. Further accurate non-invasive indices are needed to investigate sympathetic activity.

Second, it would be better to compare “good” days and “bad” days in the same patients with variant angina. However, we had no data in these patients in our present study. If we could examine whether differences in autonomic nervous activity exist in the same patient, the relation between the recurrence of attacks and autonomic nervous activity could be evaluated more accurately.

Third, the number of ischaemic episodes in the single and the multiple attack groups differed in our study, which may have affected the analysis. We therefore randomly extracted single episodes from each multiple attack group to match with episodes in the single attack group and compared the two groups by repeating the procedure. The results did not differ from those reported here.

Fourth, the coronary artery spasm may have further preceded the time detected for an ST segment elevation of 0.5 mm, defined as the onset of the angina attack in the present study. However, we could not precisely detect the moment when coronary spasm was induced from the Holter ECG. Thus we could not completely exclude the possibility that the coronary spasm and the autonomic changes were secondary to some unknown mechanism.

CONCLUSIONS

Our study shows that the HF and the LF/HF ratio transiently decrease immediately before spontaneous coronary spasm; the decrease in HF is preceded by the reduction in the LF/HF ratio, and the baseline RR interval and the LF/HF ratio are lower in patients with multiple daily ischaemic episodes than in those who have a single ischaemic episode. These findings suggest that a reduction in sympathetic activity plays a key role in determining the recurrence of transient ischaemic events caused by coronary spasm in patients with variant angina.