Pediatrics International

(2003)

45

, 407–409

Original Article

Autonomic function in Kawasaki disease with myocardial infarction: Usefulness of monitoring heart rate variability

YUTAKA KIKUCHI, YUKO SATO, KOU ICHIHASHI, HIROHIKO SHIRAISHI AND MARIKO Y MOMOI

Department of Pediatrics, Jichi Medical School, Tochigi, Japan

Abstract

Background

: Despite anticoagulant therapy, many patients with Kawasaki disease and giant coronary arteryaneurysm develop myocardial infarction. These patients have a high risk of sudden death, but the etiology isnot clear. We studied autonomic function and the possibility of malignant ventricular arrhythmia through heartrate variability.

Methods

: We studied six Kawasaki disease patients with myocardial infarction and 16 normal controls. Heartrate variability was investigated using a 24 h electrocardiogram. We assessed the standard deviation from themean of the normal R-R intervals (SDNN), the proportion of adjacent R-R intervals with a difference greaterthan 50 msec (pNN50) and the root-mean square of successive R-R differences as time–domain analysis(rMSSD). We assessed very low-frequency power, low-frequency power (LF), high-frequency power (HF)and the LF/HF ratio in frequency–domain analysis.

Results

: There was no significant difference in SDNN, but there was a significant difference in pNN50 andrMSSD. Patients with Kawasaki disease showed lower HF and higher LF/HF than normal controls.

Conclusion

: Our findings suggest that patients with Kawasaki disease and myocardial infarction showdecreased vagal activity, which could cause malignant arrhythmia.

Key words

arrhythmia, heart rate variability, Kawasaki disease, myocardial infarction.

Many cases of Kawasaki disease with giant coronary arteryaneurysm develop myocardial infarction despite anticoagu-lant therapy. These patients are at risk of sudden death, butthe etiology is not clear.

1

However, considering theetiological relationship between malignant ventriculararrhythmia and autonomic dysfunction in atheroscleroticmyocardial infarction,

2,3

it may be of value to studyautonomic function in patients with Kawasaki disease.Therefore, in the present study, we investigated theautonomic function of cases of Kawasaki disease withmyocardial infarction and discussed the etiological relation-ship with malignant ventricular arrhythmia.

Methods

Study population

The study population consisted of six patients with Kawasakidisease and myocardial infarction (Table 1). We definedmyocardial infarction as complete closure of the coronaryartery or recanalization of an occluded giant aneurysm, asdetected by coronary artery angiogram. The age of the patientsranged from 13 to 16 years (mean

±

SD 15.5

±

1.2 years). Fourpatients were boys and two were girls. The age of onset ofKawasaki disease ranged from 2 to 16 months. The rightcoronary artery was occluded in five patients and the leftcoronary artery was occluded in three patients. Two patientshad more than one occluded coronary artery. Left ventricularfunction was severely affected in three patients and normalcontraction was observed on cineangiogram in the other threepatients. Patients with multiple occluded coronary arteriestended to show severe damage of left ventricular function,whereas all patients with right coronary artery occlusionshowed normal left ventricular function. Aortocoronary arterybypass surgery was performed in three cases.

Correspondence: Yutaka Kikuchi, 3290498 Yakushiji, 33111Minamikawachi-machi, Kawachi-gun, Tochigi, Japan. Email: ykikuchi@jichi.ac.jp

Received 1 March 2001; revised 30 October 2002; accepted16 January 2003.

408 Y Kikuchi

et al

.

We studied 16 age-matched (13–14 years old; mean age13.7

±

0.5 years) control subjects without organic cardiacdisease.

Study design

All populations underwent continuous 24 h ambulatory electro-cardiographic monitoring while maintaining their normal dailyactivities and normal sleep–wake pattern. Holter tapes wereanalyzed with a MARS 8000 analyzer (Marquette, Milwaukee,USA). After arrhythmia analysis, we studied heart rate varia-bility. If an artefact or ectopic beats were interpolated, wesupplied beats using the cubic spline interpolation method.

Time–domain analysis

We calculated the standard deviation from the mean of thenormal R-R intervals (SDNN), the proportion of adjacentR-R intervals with a difference greater than 50 msec(pNN50) and root-mean square of successive R-R differencesfor time–domain analysis.

Frequency–domain analysis

We calculated very low-frequency power (VLF) from 0.0033to 0.0040 Hz, low-frequency power (LF) from 0.0040 to0.15 Hz, high-frequency power (HF) from 0.15 to 0.40 Hzand the LF/HF ratio.

Statistical analysis

Data are expressed as the mean

±

SD. We used theMann–Whitney

U

-test for statistical analysis.

P

< 0.05 wasconsidered statistically significant.

Results

Time–domain analysis

The SDNN values did not show any significant differencebetween patients with myocardial infarction and control

subjects (Table 2). Values for pNN50 and rMSSD weresignificantly decreased in patients with myocardial infarction(

P

= 0.018 and 0.0205, respectively).

Frequency–domain analysis

As shown in Table 3, there were no significant differences inVLF and LF values. However, HF was significantly lower inpatients with myocardial infarction compared to normalsubjects (

P

= 0.0363). This resulted in a significantly lowerLH/HF value in the myocardial infarction group (

P

= 0.0470).

Discussion

In Japan, between two and 12 patients with Kawasaki diseasehave died annually over the past 10 years.

4

Because most aredead on arrival at hospital, the cause of death has not beenclarified. The main cause of death in Kawasaki disease hasbeen thought to be sudden circulatory failure due to suddencoronary arterial occlusion. In contrast, the main cause ofdeath in adult myocardial infarction has been reported to bemalignant ventricular arrhythmia, such as ventriculartachycardia or following ventricular fibrillation.

5

In adultmyocardial infarction, a relationship between malignantarrhythmia and autonomic dysfunction has been established.Kleiger

et al.

reported the relationship between SDNN and

Table 1

Characteristics of cases with Kawasaki disease

Age (years) Sex Age at onset (months)

Infarction site LV function (cineangiogram) AC bypass

Case 1 16 Male 14 RCA1, LCA13 4, 5, akinesis; 3, mild hypo.Case 2 16 Male 16 LCA6 2, mild hypo.; 3, akinesis PerformedCase 3 16 Male 5 RCA1 IntactCase 4 16 Male 6 RCA1, LCA6, LCA13 6, dyskinesis; 1, 2, 3, 4, 5, moderate hypo. PerformedCase 5 13 Female 2 RCA1, RCA2 Intact PerformedCase 6 16 Female 3 RCA2 Intact

RCA, right coronary artery; LCA, left cononary artery; LV function, left vetricular function; hypo., hypocontraction; AC bypass, aortocor-onary bypass operation.

Table 2

Time–domain analysis

Control KD with MI

P

SDNN 195

±

42.1 167

±

35.3 0.173pNN50 21.6

±

9.3 10.8

±

8.2 0.0218*rMSSD 48.1

±

14.2 31.8

±

11.1 0.0205*

*Statistically significant.KD with MI, Kawasaki disease with myocardial infarction;

SDNN, standard deviation from the mean of the normal R-Rintervals; pNN50, proportion of adjacent R-R intervals with adifference greater than 50 msec; rMSSD, root-mean square ofsuccessive R-R differences for time–domain analysis.

Kawasaki disease with myocardial infarction 409

mortality rate, indicating that mortality was higher in thegroup with a low SDNN value.

3

Kent

et al.

reported astabilizing effect of the vagal nerve in myocardial infarction.

6

In recent years, we have been able to assess autonomicfunction by use of the heart rate variability method,

7

whichuses a 24 h continuous electrocardiogram record.

We studied the autonomic function of Kawasaki diseasepatients who developed myocardial infarction to assess thehypothesis that their myocardial infarction was due toautonomic dysfunction, as seen in atherosclerotic infarction.

We assessed heart rate variability time–domain analysisand frequency–domain analysis in patients with myocardialinfarction and in normal controls. In time–domain analysis,there was no difference in SDNN value between the twogroups. This suggests that there is no global heart ratevariability change in the myocardial infarction group.

8

Severemyocardial damage induces and impairs afferent and efferentautonomic nerve function and/or sinus node function.Therefore, we thought that there would be a decrease in heartrate variability in the myocardial infarction group. In thepresent study, there were no differences between the groups.This may be due to three cases who had minimal myocardialdamage and showed normal left ventricular function. Theactivity of the vagal nerve is thought to be reflected bypNN50 and rMSSD.

9,10

Therefore, low values for theseparameters indicate hypoactivity of the vagal nerve. Thus, itwould appear that our Kawasaki disease patients withmyocardial infarction have decreased vagal nerve function.In frequency–domain analysis, HF was significantly lower inthe myocardial infarction group than in the control group.High-frequency power is also thought to reflect the activityof the vagal nerve;

11,12

therefore, vagal activity in Kawasakidisease patients with myocardial infarction is lower than inthe control group. Depressed vagal nerve activity may causemyocardial infarction patients to lose myocardial stabiliza-tion and risk the development of malignant ventriculararrhythmia. Because HF was low, the LF/HF ratio was higherin the myocardial infarction group compared with the normalcontrol group. The ratio LF/HF is thought to be an indicatorof vasomotor sympathetic nerve activity.

13

The relationship

between high LF/HF levels and myocardial infarction is notclear. Because vasoconstriction increases the resistance ofperipheral blood flow, the oxygen demand of the myocardiumincreases. This, in turn, may induce myocardial ischemia andmalignant ventricular arrhythmia.

We do not have evidence of a relationship betweenKawasaki disease with myocardial infarction and malignantventricular arrhythmia, but it is clear the present study thatthese patients have an abnormal autonomic regulatorysystem. We recommend assessing ventricular arrhythmia andautonomic function by 24 h electrocardiogram during follow-up checks of Kawasaki disease patients with myocardialinfarction. In this way, the risk of sudden death can bedetermined by assessing changes in autonomic function.

References

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Table 3

Frequency–domain analysis

Control KD with MI

P

VLF 1.76

×

10

3

±

657 1.51

× 10

3

±

438 0.41LF 961

±

493 718

±

472 0.311HF 522

±

302 230

±

149 0.0363*LF/HF 2.04

±

0.66 3.74

±

1.91 0.0470*

*Statistically significant.KD with MI, Kawasaki disease with myocardial infarction;

VLF, very low-frequency power; LF, low-frequency power; HF,high-frequency power; LF/HF, low frequency to high frequencypower ratio.