Cardiovascular status after Kawasaki disease in the UK

Abstract

Objective: Kawasaki disease (KD) is an acute vasculitis that causes coronary artery aneurysms (CAA) in young children. Previous studies have emphasised poor long-term outcomes for those with severe CAA. Little is known about the fate of those without CAA or patients with regressed CAA. We aimed to study long-term cardiovascular status after KD by examining the relationship between coronary artery (CA) status, endothelial injury, systemic inflammatory markers, cardiovascular risk factors (CRF), pulse-wave velocity (PWV) and carotid intima media thickness (cIMT) after KD.

Methods: Circulating endothelial cells (CECs), endothelial microparticles (EMPs), soluble cell-adhesion molecules cytokines, CRF, PWV and cIMT were compared between patients with KD and healthy controls (HC). CA status of the patients with KD was classified as CAA present (CAA+) or absent (CAA-) according to their worst-ever CA status. Data are median (range).

Results: Ninety-two KD subjects were studied, aged 11.9 years (4.3-32.2), 8.3 years (1.0-30.7) from KD diagnosis. 54 (59%) were CAA-, and 38 (41%) were CAA+. There were 51 demographically similar HC. Patients with KD had higher CECs than HC (p=0.00003), most evident in the CAA+ group (p=0.00009), but also higher in the CAA- group than HC (p=0.0010). Patients with persistent CAA had the highest CECs, but even those with regressed CAA had higher CECs than HC (p=0.011). CD105 EMPs were also higher in the KD group versus HC (p=0.04), particularly in the CAA+ group (p=0.02), with similar findings for soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1. There was no difference in PWV, cIMT, CRF or in markers of systemic inflammation in the patients with KD (CAA+ or CAA-) compared with HC.

Conclusions: Markers of endothelial injury persist for years after KD, including in a subset of patients without CAA.

Figure 1

Circulating endothelial cells. (A) CECs were highest in the KD CAA+ group (CAA+ vs HC, 95% CI of difference in medians 8 to 44), but were not significantly higher than the CAA− group; CECs were also higher in the CAA− group versus HC (95% CI of difference in medians 4 to 12). (B) Patients with persistent CAA had even higher levels of CECs (persistent CAA vs HC, 95% CI of difference in medians 16 to 60) and higher versus CAA−. Those with regressed CAA also had high CECs (regressed CAA vs HC, 95% CI of difference in medians 0.000032 to 24) that were not significantly different from those with persistent CAA (95% CI of difference in medians −4 to 48) or the CAA− subjects. (C) There was no significant correlation between CECs and time from the acute KD episode to study: r=−0.13, 95% CI −0.23 to 0.44, p=0.36 for the CEC– group; r=0.12, 95% CI −0.40 to 0.44, p=0.50 for the CEC+ group. Horizontal lines represent median and IQR. CAA, coronary artery aneurysms; CECs, circulating endothelial cells; HC, healthy control; KD, Kawasaki disease.

Figure 2

EMP and soluble adhesion molecules. (A) KD CAA+ patients had higher CD105 EMP than HC (95% CI of difference 0.01 to 6.00×10³/mL), but there was no significant difference when the CAA+ group was compared with CAA− patients. CAA− patients did not significantly differ from HC. (B) Patients with KD with persistent CAA had the highest CD105 EMP, although this did not reach statistical significance compared with controls (95% CI of difference in median −0.00005 to 6.04×10³/mL). Patients with KD with regressed CAA had significantly higher CD105 EMP (median 2.59×10³/mL) than HC (0.00×10³/mL) (95% CI of difference in median −0.00006 to 10.49), but not compared with the persistent CAA group (95% CI of difference in median −5.68 to 10.40) or the CAA− group. (C) sVCAM-1 was significantly higher in the CAA+ group versus HC, but this was not significantly higher when compared with the CAA− group.(D) sVCAM-1 was particularly high in those with regressed CAA (Regr CAA: vs HC (95% CI of difference in median 32.3 to 144.6 ng/mL) and vs CAA−), but was not different from those with persistent CAA (95% CI of difference in median −44.4 to 111.1 ng/mL). (E) sICAM-1 was higher in the KD CAA+ group (vs HC (95% CI of difference in median 1 to 59 ng/mL) and vs CAA−). (F) sICAM-1 was highest in those with persistent CAA (Pers CAA: vs HC (95% CI of difference in median 2 to 86 ng/mL) and higher than the CAA− group). There was no difference in sICAM-1 levels between the persistent and regressed CAA groups (95% CI of difference in median −76 to 31 ng/mL), and no significant difference between Regr CAA and controls (95% CI of difference in median −11 to 52 ng/mL). Horizontal lines represent median and IQR. CAA, coronary artery aneurysms; EMP, endothelial microparticles; HC, healthy control; KD, Kawasaki disease; Pers, persistent; Regr, regressed; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular cell adhesion molecule.

Figure 3

PWV versus age. There was a strong positive association between age and carotid-femoral PWV for all subject groups: r²=0.65 for controls, r²=0.62 for KD CAA− and r²=0.73 for KD CAA+; p<0.0001 for all. Analysis of covariance of the carotid-femoral PWV slope did not show any statistically significant difference from controls (dashed line) for KD CAA− patients (solid black line, p=0.87) or KD CAA+ patients (red line, p=0.66). CAA, coronary artery aneurysms; HC, healthy control; KD, Kawasaki disease; PWV, pulse-wave velocity.