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Re: Re: Coronary endothelial dysfunction after Kawasaki disease

Dear Editor:

We appreciate the kind comments of Dr Mitani regarding our article in the March 2000 issue of Heart and for sharing their experiences with us.[1]

In group 1 and 2 patients who had regressed coronary aneurysm after Kawasaki disease, there was significantly more vascular constriction with acetylcholine and poorer dilatation with isosorbide dinitrate at the regressed site, than in group 3 patients who had no coronary artery lesions after Kawasaki disease.

Fourteen patients in group 1 and group 2 in the acute stage of illness had coronary artery lesions on one side of the coronary artery but no coronary artery lesion on the opposite side.

We also evaluated the vascular function of these sites (n = 19) using intracoronary infusion of acetylcholine chloride and isosorbide. The mean (SD) change in the coronary artery diameter after infusion of acetylcholine was 12.5 (3.0)% in group 1 and 2, and 11.3 (5.6)% in group 3. The mean (SD) change in the coronary artery diameter after infusion of isosorbide dinitrate was 17.3 (9.5)% in group 1 and 2, and 18.0 (8.2)% in group 3. There was no significant difference in responses to the infusion of either acetylcholine or isosorbide dinitrate between these two groups.

These findings suggested that such coronary arteries had finctionally normal endothelium and smooth muscle even in patients with a history of severe Kawasaki vasculitis.

The coronary arteries in group 3 patients had normal responses to the infusion of either acetylcholine or isosorbide dinitrate, according to the analysis of multiple coronary artery segments involving proximal coronary artery segments. We assessed differences in responses to the infusion of acetylcholine or isosorbide dinitrate between proximal coronary artery segments and distal coronary artery segments in group 3 patients and in controls. The mean (SD) change in the coronary artery diameter after infusion of acetylcholine was 11.9 (3.5)% at the proximal artery coronary segments and 12.8 (4.0)% at the distal coronary artery segments in group 3. The mean (SD) change in the coronary artery diameter after infusion of isosorbide dinitrate was 16.8 (4.2)% at the proximal coronary artery segments and 17.1 (8.0)% at the distal coronary artery segments in group 3.

These results suggested that there was no significant difference in responses to the infusion of either acetylcholine or isosorbide dinitrate between the proximal coronary artery segments and the distal coronary artery segments in group 3 patients. Similar findings were found in the control patients.

In a new study,[2] we investigated the vascular morphology of the coronary artery, in 6 Kawasaki disease patients who had completely normal first coronary angiography findings, using intravascular ultrasound imaging; we found no differences in wall morphology between the proximal coronary artery segments and the distal coronary artery segments.

From the basis of our studies, we conclude that long-term persistent coronary aneurysms and regressed coronary aneurysms after Kawasaki disease exhibit vascular dysfunction.[1-5] These patients should be counseled to avoid potential risk factors for atherosclerosis, and they should be advised that long-term follow-up is needed into adulthood. However, patients with normal coronary arteries after Kawasaki disease had no significant difference from the controls in response to either acetylcholine or isosorbide dinitrate infusion. These findings suggested that such coronary arteries had normal function of the endothelium and smooth muscle even in the long term.

References

(1) Iemura M, Ishii M, Sugimura T, Akagi T, Kato H. Long- term consequences of regressed coronary aneurysms after Kawasaki Disease: vascular wall morphology and function. Heart 2000;83:307-11.

(2) Ishii M, Hashino K, Iemura M, Yamakawa R, Muta H, Himeno W, Akagi T, Kato H. Long-term consequences of coronary aneurysms after Kawasaki disease: vascular wall morphology and endothelium function (abstract). J Am Coll Cardiol 2000;35:513A.

(3) Yamakawa R, Ishii M, Sugimura T, Akagi T, Eto G, Iemura M, Tsutsumi T, Kato H. Coronary endothelial dysfunction after Kawasaki disease: evaluation by intracoronary injection of acetylcholine. J Am Coll Cardiol 1998;31:1074- 80.

(4) Sugimura T, Kato H, Inoue O, et al. Vasodilatory response of the coronary arteries after Kawasaki disease: evaluation by intracoronary injection of isosorbide dinitrate. J Pediatr 1992;121:684-8.

Send letter to journal:
Re: Coronary Endothelial Dysfunction after Kawasaki Disease

Iemura et al's hypothesis that endothelial dysfunction is associated with coronary aneurysms which have regressed after Kawasaki disease (KD) is interesting[1]; however, there are two issues with respect to their study design that need to be considered, in addition to the issues reported before.[2, 3]

(1) Is endothelial dysfunction associated with regressed coronary aneurysms per se late after KD?

Iemura et al showed that acetylcholine-induced vasodilatation is impaired in regressed coronary aneurysms (groups 1 and 2) but there is preserved vasodilatation in patients without coronary involvement during the acute illness of KD (group 3). This could be explained either by the direct effect of the regressed aneurysm or the difference among the study groups (groups 1 and 2 versus group 3). The Kawasaki vasculitis was severe enough to cause coronary aneurysms in some segments during the acute illness.

Although in Fig 1 Iemura et al showed that there is acetylcholine-induced vasoconstriction in the regressed aneurysm, readers might note that the rest of the segments in the right coronary artery without coronary lesions from the onset, including segments remote from the regressed aneurysms, also seem to constrict in response to acetylcholine. This might suggest that the regressed aneurysm per se does not impair endothelial function after KD.

Iemura et al did not present any data analysing the acetylcholine-elicited responses in normal segments from disease onset in groups 1 and 2; therefore the alternative hypothesis remains possible i.e. that coronary segments, regardless of their association with regressed aneurysms, constrict in response to acetylcholine in patients with a history of severe Kawasaki vasculitis. Consistent with this hypothesis, previous reports concluded that endothelial function is impaired in unaffected coronary segments and brachial arteries (usually uninvolved with aneurysms during the acute illness) in patients with severe acute Kawasaki vasculitis in the long term follow up period:

1.5-12.5 years (mean (SE) 6.5 (1.1)) after acute KD in Mitani et al[2]
5.3-17.1 years (median 11.3) after KD in Dhillon et al[4]
16-28 years old (mean 22) at the time of examination in Kamiya et al[5]
1-14 years old (median: 3.5) at the time of examination in Sano et al[6]

(2) Is endothelial function entirely preserved in KD patients without coronary involvement during the acute illness (group 3)?

This is an issue that we did not specifically address in our previous study.[2] Iemura et al showed that coronary arteries normally dilate in response to acetylcholine in patients without coronary lesions during the acute illness (group 3) on the basis of analysing multiple coronary segments.[1] However, in KD patients some coronary segments (ie, proximal segments) are characteristically more susceptible to severe abnormalities than others in terms of morphological, angiographic findings and vasomotor function.[2, 7, 8] Abnormal vasomotor function might be unmasked by specifically focusing on some "susceptible" segments in group 3, as we did in uninvolved proximal coronary segments in patients with coronary aneurysms in other segments.[2] An alternative hypothesis that some susceptible segments are associated with impaired acetylcholine-induced vasodilatation even in group 3 remains to be tested.

Iemura et al's conclusion might not be consistent with a previous report showing that endothelial function is impaired in KD patients without aneurysms in any segment during the acute illness.[4] This inconsistency remains to be addressed.

References

1. Iemura M, Ishii M, Sugimura T, et al. Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function. Heart 2000;83:307-11.

2. Mitani Y, Okuda Y, Shimpo H, et al. Impaired endothelial function in epicardial coronary arteries after Kawasaki disease. Circulation 1997;96:454-61.

3. Mitani Y. Coronary endothelial dysfunction after Kawasaki disease. J Am Coll Cardiol 2000;35:821-3

4. Dhillon R, Clarkson P, Donald AE, et al. Endothelial dysfunction late after Kawasaki disease. Circulation 1996;94:2103-6.

5. Kamiya Y, Onouchi Z, Hamaoka K. Arteriosclerosis long after Kawasaki disease: endothelial function. Acta Cardiol Paediat Jpn 1997;13:252 (Japanese).

6. Sano T, Tagawa T, Itagaki Y, et al. Endothelial dysfunction after Kawasaki vasculitis. Jpn Circ J 1999;63:338 (Japanese).

7. Naoe S, Takahashi K, Masuda H, et al. Kawasaki disease: with the particular emphasis on arterial lesions. Acta Pathol Jpn 1991;41:785-97.