COMMENTARIES

Patients after Kawasaki Disease and Premature Atherosclerosis: A Surge of Accumulating Evidence

Nobutaka Noto, MD., Ph.D., FACC, Tomoo Okada, M.D., Ph.D, and Hideo Mugishima, M.D., Ph.D., Department of Pediatrics, Nihon University School of Medicine, 30-1 Oyaguchi, Itabashi-ku, 173-8610, Japan, Tel: +81-3-3972-8888(2442), Fax: +81-3-3957-6186, Email: info@noto-clinic.com

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology in infants and children. First described in Japan in 1967, KD has been described worldwide among children of all races and ethnicities. More than 4,000 hospitalizations associated with KD were reported in 2000 in the United State [1]. In Japan, a national survey of KD has been performed every 2 years since 1970. The most recent nineteenth survey covered 2005 and 2006 and showed that there were 10,041 and 10,434 new cases of KD in those years, respectively. As of 2006, there have been 225,682 patients since 1970 [2]. Therefore, patients diagnosed with KD in the sixties and seventies have already reached adulthood. The increased incidence of young adults with a history of KD during childhood has been accompanied by a new problem of an association between post-KD lesions and atherosclerosis.

    Clinical and subclinical inflammation of coronary and systemic arteries after KD may form the substrate for long-term functional and structural abnormalities and increase the risk of premature atherosclerosis. In fact, some studies have demonstrated that alterations in the lipid profile and generalized endothelial dysfunction persist for a long time after the clinical resolution of KD [3,4]. There is accumulating evidence that flow-mediated dilatation (FMD) of the brachial artery induced by reactive hyperemia, a noninvasive marker of endothelial function, is abnormal in post-KD patients with or without coronary artery lesions (CAL) [5,6]. Furthermore, some studies have shown that adverse cardiovascular profiles, characterized by proatherogenic alteration of lipid profiles [7], increased intima-media thickness (IMT) of the carotid artery [8,9], and arterial stiffness [10,11], occur in patients after KD with CAL. KD patients with CAL have been shown to have ongoing systemic inflammation years after disease onset, as evidenced by high-sensitivity C-reactive protein (hs-CRP) levels that are significantly higher than those seen in normal age-matched children or in patients with KD without CAL. Inflammatory mediators, such as hs-CRP, may themselves promote atherosclerosis [12]. In contrast, a recent study indicated that KD patients have some abnormalities that are risk factors for atherosclerosis, but there is no long-term systemic arterial endothelial dysfunction regardless of the degree of coronary artery involvement [13,14]. With respect to the noninvasive methods of investigating endothelial dysfunction and vascular structural changes suggestive of atherosclerosis after KD, data are conflicting.

    As for previous histological findings of KD, only there is one immunohistochemical study of the coronary artery of a pediatric patient with KD without coronary dilatation, who had died of unrelated causes. Compared with control subjects, the coronary artery intima was mildly thickened, and platelet-derived growth factor-α, transforming growth factor-β1, and inducible nitric oxide synthase were expressed in the intimal smooth muscle cells [15]. Likewise, a pathological study of KD patients older than 15 years of age without coronary aneurysms demonstrated new intimal thickening in addition to pre-existing intimal thickening that had been caused by arteritis in the acute phase [16]. However, Suzuki et al. reported that many years after the onset of KD there were no inflammatory cell invasions that would suggest persisting coronary artery vasculitis in the coronary arteries. Furthermore, there was no significant macrophage infiltration or foamy cell formation in KD coronary arteries 3 to 12 years after the onset of KD [17]. In addition, Fukazawa et al. showed that findings of vascular senescence closely associated with atherosclerosis in KD patients 3 to 11 years old with aneurysms were severe in the vasculature of the vasa vasorum as well as in intima endothelial cells. The few macrophages and lack of lipid deposition in KD patients, which was distinct from adult atherosclerosis and coronary arteries less than 10 years after the onset of KD [18]. Inevitably, adult atherosclerosis progression originates from the intimal wall of the arteries for the atherosclerotic change. In contrast, for the KD patients with CAL, sclerotic change may develop earlier from the adeventitia vasa vasorum [17]. Intriguingly, a rabbit model resembling KD, in which allergic coronary arteritis was induced by serial horse serum injections, typically show panarteritis. Intimal thickness with small muscle cell SMC persisted even in the chronic phase, when inflammatory cells have subsided. When a high fat diet was fed to this allergic arteritis rabbit model, significant amounts of typical atherosclerotic plaque appeared [19]. This finding suggested that post-arteritis tissue may more easily develop atherosclerotic changes. Therefore, further pathological studies in coronary arteries of adult-KD patients are highly warranted.

    Among patient characteristics that influence vascular health, dyslipidemia is prevalent in patients with KD with or without CAL well beyond the time that the clinical disease has resolved. McCrindle et al. showed that KD patients 10 to 20 years of age had lower apolipoprotein A1 levels than the control subjects [13]. Earlier studies have shown that HDL cholesterol levels may be depressed acutely [4], but there is controversy whether this decrease persists over the long term. Mitani et al. showed that there were no differences between patients with KD among 10 years after the onset and control subjects with regard to total cholesterol and HDL cholesterol levels [12]. However, Cheung et al. reported that KD patients among 10 year olds with or without CAL had significantly higher levels of apolipoprotein B and lower levels of HDL cholesterol compared with control subjects [7]. Therefore, no consensus has been reached whether dyslipidemia in KD patients over the long term after the clinical resolution causes a higher risk of atherosclerosis than that in the general population.

    Due to these conflicting reports, concerns have been raised not only whether KD patients are at risk for premature atherosclerosis in adulthood but also whether the vascular remodeling process underlying atherosclerosis in KD differs from that in the general population. Although the exact reasons for these conflicting results remain undetermined, differences in study populations, methodology, and latent cardiovascular risk factors (CRFs) including age, pubertal status, and systemic inflammation may play a role. Age is of particular interest because the atherosclerotic process begins in childhood [20]. We speculated that endothelial dysfunction and the propensity for subclinical atherosclerosis gradually appear during adolescence and then rapidly increase with age, particularly in post-KD patients with CAL, including aneurysm, stenosis, and occlusion, who show diffuse vascular inflammation during the acute phase. To test this hypothesis, we examined the relationship between age and progression of endothelial dysfunction (FMD) and subclinical atherosclerosis (age-adjusted % normal IMT, Elastic modulus) in a case-control study comparing post-KD patients with CAL to healthy control subjects across a wide age range (8-42 years). Our findings suggest that the propensity for subclinical atherosclerosis was increased in post-KD patients above teenage with CAL. Of note, our study population consisted of relatively older subjects, whose mean age and mean elapsed time from initial onset were 20.5 and 18.6 years, respectively [21]. In contrast, the study populations in most previous studies consisted of subjects with mean ages in the early teens [6,9,12,13,22]. Therefore, these previous studies may not accurately demonstrate the long-term structural and functional alterations of systemic arteries in adult-KD patients.

    The underlying mechanisms of age-related endothelial dysfunction and the propensity for subclinical atherosclerosis in subjects with KD remain unclear. Age-related changes in vascular free radical production, oxidative stress, and the catabolism of endothelium-derived regulators of vasomotor tone can result in a reduced FMD response and a propensity for subclinical atherosclerosis [23]. Furthermore, persistent low-grade inflammation late after the acute phase of KD may contribute to functional alterations and the subsequent remodeling process during the convalescent phase of KD. In addition, a strong association exists between adverse lipoprotein levels and the initial stages of atherosclerosis in adolescents and young adults, advanced atherosclerotic lesions may be enhanced with age [20]. Since young adults often become sedentary once they leave school and physical activities are generally restricted in KD patients with CAL, it is likely that subtle risk factors cluster in individual KD patients and the process of atherosclerosis is enhanced in the presence of CRFs over time.

    Recently, there has been a surge of accumulating evidence associating post-KD lesions with atherosclerosis because nearly half of the post-KD patients have reached adulthood. Among KD patients with CAL, impairment of coronary artery structure and function have been well documented. However, it is still too early to determine the conclusions whether post-KD patients in whom coronary abnormalities were never detected are at risk for premature atherosclerosis later in adulthood. Indeed, we will not definitively determine whether post-KD patients are really at higher risk for atherosclerosis later in adulthood until the early Japanese cohort reaches middle and older age. To date, all patients with a history of KD should be carefully assessed for factors promoting atherosclerosis, including obesity, hypercholesterolemia, systemic hypertension, and smoking.

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