Background/Purpose:

Kawasaki disease (KD) is a self-limited acute vasculitis of young children, and coronary artery aneurysms (CAA) are the most significant complication. Despite appropriate treatment (intravenous immunoglobulin and aspirin), CAA will develop in 5-9% of cases. The etiology of the vascular inflammation is still unknown. We previously reported that the transforming growth factor-β (TGF-β) signaling pathway plays an important role in the development of CAA. Galectin-3 (Gal-3) is a novel cardiac fibrosis marker associated with cardiovascular events, and also regulates tissue inflammation and fibrogenesis, which is mediated through the TGF-β pathway. However, the association of Gal-3 with CAA in KD patients has not been previously reported.

Methods:

We measured Gal-3 levels in the plasma of 69 young adults with a history of KD (AKD) and 12 acute (pre-treatment) pediatric KD patients (PKD) by enzyme-linked immunosorbent assay (ELISA). AKD subjects were classified as having CAA or normal coronary arteries (CA), based on coronary artery diameter measured by CT or standard coronary angiography. Classification of PKD subjects was based on coronary artery internal diameter measured by transthoracic echocardiography normalized for body surface area and expressed as standard deviation units for the mean (Z-scores). Z-max was defined as the largest Z-score of either the right or left anterior descending coronary artery during the first 8 weeks after disease onset. Data were analyzed by the Kruskal-Wallis test using Prism software, p<0.05 was considered to be statistically significant.

Results:

AKD subjects with normal CA had significantly lower Gal-3 levels (median 10.0ng/ml, n=58) compared to PKD subjects with CAA (18.1ng/ml, n=8), PKD subjects with normal CA (14.4ng/ml, n=4), and AKD subjects with CAA (14.9ng/ml, n=11) (p=0.0006). Overall, there was a trend toward higher Gal-3 levels in PKD vs AKD subjects, and in subjects with CAA vs normal CA (Figure).

Conclusion:

Gal-3 levels in both PKD and AKD CAA subjects tended to be higher than in normal CA subjects. Gal-3 tethers the TGF-β receptor on the cell surface, and leads to increased TGF-β signaling resulting in endothelial/epithelial to mesenchymal transition (EMT). Increased TGF-β signaling and EMT are implicated in CAA formation based on KD autopsy studies. In addition, secreted Gal-3 binds to extracellular matrix proteins and acts as a cell adhesion molecule that promotes inflammation. Thus, Gal-3 may participate in the pathogenesis of CAA formation but whether higher Gal-3 levels are causal remains to be determined. Further investigation with larger numbers of PKD subjects is in progress.