Prevention and treatment of coronary artery dilation with doxycycline in Kawasaki disease – the DEAL study results

Kawasaki disease (KD) is the leading cause of acquired heart disease in children of the developed world. It presents as an acute self-limiting illness with fever, inflammation of the skin and mucous membranes, and a multisystem vasculitis including the coronary arteries. Even following current therapeutic guidelines, 25-30% of children with KD will develop coronary artery dilation (CADil). Patients with CADil may face permanent and potentially devastating complications, such as coronary vasculopathy, myocardial infarction and even death. Currently there is no available treatment or prevention of CADil in children with KD. In the acute phase of KD, activated macrophages and lymphocytes in the wall of the coronary arteries induce matrix metalloproteinase (MMP) activity that is responsible for elastin degradation resulting in CADil. Doxycycline (a common antibiotic and a known inhibitor of MMPs) was shown to decrease MMP-9-mediated coronary elastin breakdown and improve coronary outcome in an animal model KD. Our published data demonstrate that pro- MMP-9 is elevated in children during the acute phase of KD when CADil may occur. Our preliminary observations indicate that doxycycline may improve the progression of CADil in children with KD. Based on these data, we will test the following hypotheses: a 3-week course of oral doxycycline treatment during the acute phase of KD will prevent the progression of CADil, and prevent elastin degradation by inhibiting MMP activity demonstrated by decreasing level of circulating soluble elastin fragments and MMPs.

Aim 1: We will evaluate the efficacy of doxycycline to prevent CADil by assessing the size of coronary arteries by echocardiogram before, during and after doxycycline treatment in children during the acute phase of KD. We will compare the diameter of the coronary arteries to controls of children with acute KD and no doxycycline treatment. Aim 2: We will identify serum markers of CADil in KD. We will use a tiered approach including a global proteomic screen, evaluation of previously established markers such as SEF and MMPs, and confirmation of candidate proteins. We will assess the correlation of serum concentration of candidate proteins with the degree of CADil and the response to doxycycline. Aim 3: We will determine the mechanism of doxycycline in preventing elastin degradation using a porcine aortic organ culture model. We will assess the inhibitory effect of doxycycline on elastin degradation by measuring the elastin content in the vessel wall, and will assess the change in candidate markers of CADil in the supernatant.