No abstract

; and The Z-score Project 2nd Stage Study Group IMPORTANCE Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). OBJECTIVE To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. DESIGN, SETTING, AND PARTICIPANTS This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. MAIN OUTCOMES AND MEASURES The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, Ն5 to <10; actual internal diameter, <8 mm), and large (z score, Ն10 or Ն8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. RESULTS Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. CONCLUSIONS AND RELEVANCE Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.

Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/ protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.

Objective-We evaluated the role of angiotensin II (AII) in a marrow-derived macrophage-driven model of atherosclerosis. Methods and Results-Eight-week-old C57BL/6 wild-type mice were reconstituted with bone marrow harvested from apolipoprotein E-deficient (apoEϪ/Ϫ3 apoEϩ/ϩ) or wild-type for apoE gene (apoEϩ/ϩ3 apoEϩ/ϩ) mice. At 20 weeks, mice were exposed to either AII (1000 ng/kg per minute subcutaneously) or saline for 2 weeks. Animals did not differ in body weight, blood pressure, cholesterol/triglycerides, or peripheral blood monocyte counts. ApoEϪ/Ϫ3 apoEϩ/ϩ mice exposed to AII had 3-fold greater atherosclerotic area than saline-treated apoEϪ/Ϫ3 apoEϩ/ϩ mice. By contrast, AII did not affect atherosclerosis in apoEϩ/ϩ3 apoEϩ/ϩ mice. Macrophage-positive areas were increased by AII in mice reconstituted with either apoE-deficient or apoE-competent marrow. AII also significantly increased fragmentation of elastin laminae in both apoEϪ/Ϫ3 apoEϩ/ϩ and apoEϩ/ϩ3 apoEϩ/ϩ mice. In vitro, AII caused greater increase in monocyte chemoattractant protein-1-stimulated migration of macrophages harvested from AII-infused versus saline-infused mice. Conclusions-The current studies reveal that AII has both initiating and sustaining proatherogenic effects. By promoting macrophage migration into the vascular intima, AII is pivotal in initiating atherosclerosis; by promoting elastin breaks, a novel mechanism implicated in migration and proliferation of smooth muscle cells, AII may be pivotal in subsequent development and expansion of atherosclerotic lesion. Key Words: atherosclerosis Ⅲ angiotensin II Ⅲ macrophage E levation in angiotensin II (AII) amplifies atherosclerosis in animal models; 1-3 conversely, AII inhibition lessens progression of atherosclerotic lesions in animal models and reduces the number of acute cardiovascular sequelae of atherosclerosis in humans. 4 -6 The underlying mechanisms for these effects remain unclear. AII promotion of atherosclerosis is thought to involve activation of the proinflammatory response of the vessel wall while its inhibition quells this response. Specifically, AII has been shown to stimulate adhesion molecules in vascular endothelium including vascular cell adhesion molecule-1, intercellular adhesion molecule-1, chemotactic factors including monocyte chemoattractant protein-1 (MCP-1), cytokines, and growth factors including IL-1, tumor necrosis factor-␣, colonystimulating factor, platelet-derived growth factor, transforming growth factor-␤, as well as reactive species that promote monocyte infiltration and smooth muscle migration into the subendothelial space. 7-11 These cells then take-up lipids to become foam cells that coalesce into atherosclerotic lesions. The pivotal role of the monocyte/macrophage in the initiation and progression of the atherosclerotic lesion has been demonstrated by studies showing that disruption of cytokines, chemokines, and adhesion molecules that lessen monocyte/macrophage recruitment also abrogate lesion development. 8 -11 Although much of the pro-atherog...