The Journal of Pediatrics
Volume 151, Issue 3 , Pages 225-228, September 2007

Are Patients with Kawasaki Disease at Risk for Premature Atherosclerosis?

Children’s Hospital, Department of Cardiology, Boston, Massachusetts

Article Outline

Abbreviations: IMT, Intima-medial thickness, IVIG, Intravenous gamma globulin, KD, Kawasaki disease

 

Kawasaki, disease (KD) is a childhood vasculitis of unknown cause characterized by fever, rash, enanthem, conjunctival injection, extremity changes, cervical adenopathy, and laboratory test results reflecting intense systemic inflammation.1 First described in Japan in 1967, KD has been described worldwide among children of all races and ethnicities. In the United States, more than 4000 hospitalizations associated with KD were reported in 2000,2 and KD has replaced rheumatic fever as the leading cause of acquired heart disease in children.3 Clinical and epidemiologic features suggest an infectious trigger, with expression of clinical disease likely modified by genetic susceptibility.2 Conventional therapy for KD includes administration of aspirin and intravenous gamma globulin (IVIG) within the first 10 days of illness, and ideally within the first week. The goal of therapy in the acute phase of KD is to reduce inflammation in the coronary artery wall and prevent coronary artery thrombosis.

See related articles, p 239 and p 244

The acute signs and symptoms of KD are self limited, and the disease only rarely recurs. However, the vascular inflammation that accompanies this disease is diffuse and may have long-term sequelae. The most severely affected children have coronary artery aneurysms that can lead to myocardial infarction, ischemic cardiomyopathy, and sudden death.4, 5 Coronary artery aneurysms defined by Japanese Ministry of Health criteria occur in up to 25% of untreated children; treatment with high-dose IVIG in the acute phase of the disease reduces the risk of aneurysms by approximately 5-fold.6 More subtle coronary artery dilation occurs among those who do not meet Japanese Ministry of Health criteria, however. When coronary artery dimensions are adjusted for body surface area, more than 1 in 4 children classified as having normal coronary arteries by Japanese Ministry of Health criteria have at least 1 coronary artery dimension more than 2 standard deviations above the expected mean.7 Thus coronary artery dilation in KD is even more prevalent than originally suspected. Clinical or subclinical inflammation of the coronary and systemic arteries may form the substrate for longer-term functional and structural abnormalities and increase the risk of premature atherosclerosis.8, 9, 10 A number of noninvasive methods have been developed to study endothelial function and structural changes suggestive of atherosclerosis. Brachial artery flow–mediated dilation has been studied widely and can be safely applied to large and varied groups of patients including children.11 The brachial artery dilation response to increased shear stress is mainly due to endothelial release of nitric oxide and correlated with coronary endothelial function.12 An alternative noninvasive method is measurement of arterial stiffness by pulsed-wave analysis or arterial tonometry, which is now recognized as important in predicting coronary artery disease.13 Structural arterial abnormalities are indicated by increased thickness of the intimal-medial portion of the carotid artery measured by B-mode ultrasonography. Increased carotid artery intima-medial thickness (IMT) has been shown to reliably indicate the presence of atherosclerosis.14 Tests of arterial structure and function have been applied to patients with a history of KD with and without detectable coronary artery aneurysms in the acute phase of the illness.

This issue of The Journal of Pediatrics includes 2 small studies with conflicting inferences about arterial health after KD. Dalla Pozza et al15 compared carotid artery IMT among 48 patients with KD and 28 control subjects of similar age and sex. Carotid artery IMT, expressed as both unadjusted dimension and z-score, was greater among patients with KD than control subjects; within the KD group, the 15 patients with a history of coronary artery aneurysms had greater carotid artery IMT than the 5 children without coronary artery lesions. Patients with KD and control subjects had similar baroreceptor sensitivity and levels of established risk factors for adult atherosclerotic heart disease, including body mass index, blood pressure, and lipid profile. These authors infer that patients with KD have subclinical atherosclerosis and may be at risk even in the absence of persistent coronary artery abnormalities.

In contrast, McCrindle et al16 report that 52 patients with KD, compared with 60 healthy control subjects, had similar systemic endothelial function, assessed by flow-mediated brachial artery reactivity. Furthermore, flow-mediated dilation was not significantly related to either patient or KD characteristics, similar findings to those in the authors’ earlier report with fewer patients.17 In the past, these authors reported that patients with KD had a more adverse cardiovascular risk profile, with higher blood pressure and greater adiposity, compared with control children.17 In the current study, few differences in atherosclerotic risk factors were found between patients with KD and healthy control subjects, with the exception that patients with KD in this study had significantly lower apolipoprotein A1 and hemoglobin A1c levels, as well as lower blood pressure, but with less nocturnal decline. Markers of the systemic inflammatory response were not measured.

To help to interpret the importance of these contradictory manuscripts, it is useful to place them in the context of prior work in the field. We will review evidence for vascular changes according to coronary artery status, because the severity of vasculitis might be expected to affect the future risk of atherosclerotic vascular disease.

Patients with persistent coronary artery aneurysms have suffered the most severe arterial insult.18 In such patients, compared with control patients, the carotid arterial wall has been reported to have a higher IMT and lower distensibility,19, 20 although others have not confirmed these findings.21 Abnormalities of arterial function have also been reported. Ikemoto et al21 demonstrated endothelial dysfunction, as indicated by decreased brachial artery flow–mediated dilation, in patients with persistent coronary artery lesions. Two earlier studies on endothelial function in patients with KD reported similar results.22, 23 Patients with persistent aneurysms have been shown to have ongoing systemic inflammation years after disease onset, as evidenced by C-reactive protein levels that are significantly higher than those seen in normal age-matched children or among patients with KD without aneurysms or with regressed aneurysms.24 Inflammatory mediators, such as C-reactive protein, may themselves promote atherosclerosis.25

Patients whose aneurysms have regressed to normal diameter represent an intermediate group. By 2 years after disease onset, approximately half of coronary artery aneurysms will have regressed to normal lumen diameter on angiography.4, 26 Regressed aneurysms are characterized by fibrous intimal thickening on histopathologic examination27, 28, 29 and by marked symmetric or asymmetric myointimal thickening on intravascular ultrasonography.30, 31 Indeed, initial coronary artery dimension has been shown to be highly related to coronary artery IMT by intravascular ultrasonography more than 10 years later.32 In addition to abnormal vascular structure, regressed coronary artery aneurysms have abnormal endothelial function, with reduced vascular reactivity to isosorbide dinitrate and constriction with acetylcholine.33, 34, 35, 36 The proximal and peripheral arterial beds have also been reported to be stiffer among patients with KD with persistent or regressed aneurysms than in normal control subjects,20, 37, 38 with aortic pressure waveforms late after illness onset resembling those in the elderly.37

In the era of IVIG therapy, most children with KD do not have development of coronary artery aneurysms. With careful late clinical follow-up, such patients have morbidity and mortality rates that are similar to those in the normal population.39 However, data are conflicting on preclinical vascular changes in patients with KD in whom coronary abnormalities were never detected. Some studies in this subgroup have shown preclinical abnormalities in endothelial function, arterial stiffness, and myocardial flow reserve.20, 21, 22, 40, 41, 42, 43 For example, compared with normal subjects, they have been reported to have depressed endothelium-dependent brachial artery reactivity,22, 23 as well as higher brachial-radial artery mean pulse wave velocity, suggesting increased arterial stiffness.44, 45 Others have reported endothelial dysfunction only among patients with persistent coronary artery lesions,21 and that endothelial dysfunction is worst among those with coronary artery aneurysms.23 With respect to structural abnormalities, data are once again conflicting. Some investigators have found no difference in carotid artery IMT between patients with KD and control subjects,21, 23 consistent with the hypothesis that functional abnormalities might precede those of structure. In contrast, Cheung et al20 found increased carotid artery IMT even among patients with KD with normal coronary arteries, compared with control subjects. Cardiac catheterization studies also have been conflicting with regard to whether endothelium-dependent relaxation is impaired in “normal” epicardial coronary artery segments of patients with KD.46, 47 Of note, patients with KD without a history of coronary artery dilation appear to have lower myocardial flow reserve and higher total coronary artery resistance than control subjects.42, 43 The only immunohistochemical study of the coronary arteries of a patient with KD without coronary dilation was performed in a child who died of unrelated causes48; 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.

How can we reconcile the conflicting literature on long-term vascular health among patients who have had KD, including the two most recent contributions in The Journal?15, 16 Studies of arterial structure and function in KD are handicapped by small sample sizes and limited power; similar studies in adults characteristically include hundreds and even thousands of patients.49, 50, 51 Statistical significance can be reached only when differences between groups are large or sources of variance other than KD-related vascular changes are small. Unfortunately, potential sources of variation are numerous and include both technical factors associated with test performance and patient characteristics.11 Among patient characteristics that influence vascular health, dyslipidemia is prevalent in patients with KD with or without overt coronary artery sequelae well beyond the time that the clinical disease has resolved.38, 52, 53 Other patient factors influencing vascular health include hypertension, diabetes mellitus, smoking, obesity, systemic inflammation, age, pubertal status, and sex. It is impossible to adjust for all of these factors in a small series of patients. Furthermore, the higher prevalence of risk factors for future atherosclerotic coronary artery disease among youth in North America compared with in Japan and other Asian countries could have affected the ability of McCrindle et al16 to detect vascular changes related to KD.

It is unlikely that a large international study of vascular health in children with KD will be performed in the near future. Thus multiple small studies must be viewed in the aggregate to assess the arterial health and guide management of patients with KD. Among those with persistent or regressed coronary artery aneurysms, coronary artery structure and function are well documented to be impaired; therefore the presence or absence of abnormalities in other systemic arteries does not affect their need for aggressive management of other risk factors. Further investigation is needed, however, before conclusions can be reached regarding the impact of KD on vascular health among those in whom coronary artery changes were never detected. Indeed, we will not know with certainty whether “always normal” patients with KD are at higher risk for atherosclerosis until early Japanese cohorts reach middle and older age.54 Until published data allow evidence-based practice, all patients with a history of KD should be carefully assessed for risk factors for future atherosclerotic heart disease, including dyslipidemia, hypertension, smoking, obesity, diabetes mellitus, and sedentary lifestyle. Guidance for clinicians is provided by recent American Heart Association recommendations for cardiovascular risk reduction, with thresholds for counseling and pharmacologic management in patients with KD tailored to the degree of coronary artery involvement.55

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PII: S0022-3476(07)00460-X

doi:10.1016/j.jpeds.2007.05.011

Refers to article:

  • Subclinical Atherosclerosis, but Normal Autonomic Function after Kawasaki Disease , 28 July 2007

    Robert Dalla Pozza, Susanne Bechtold, Simon Urschel, Rainer Kozlik-Feldmann, Heinrich Netz
    The Journal of Pediatrics September 2007 (Vol. 151, Issue 3, Pages 239-243)

  • Are Patients after Kawasaki Disease at Increased Risk for Accelerated Atherosclerosis? , 28 July 2007

    Brian W. McCrindle, Susan McIntyre, Christopher Kim, Tammy Lin, Khosrow Adeli
    The Journal of Pediatrics September 2007 (Vol. 151, Issue 3, Pages 244-248.e1)

The Journal of Pediatrics
Volume 151, Issue 3 , Pages 225-228, September 2007

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