Active Remodeling of the Coronary Arterial Lesions in the Late Phase of Kawasaki Disease

Suzuki, Atsushi; Miyagawa‐Tomita, Sachiko; Komatsu, Keiko; Nishikawa, Toshio; Sakomura, Yasunari; Horie, Toshinobu; Nakazawa, Makoto

doi:10.1161/01.cir.101.25.2935

Cited by 173 publications

(139 citation statements)

References 14 publications

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“…In fact, pathological studies have revealed that CAL in KD are characterized by subendothelial oedema, vascular EC damage and the infiltration of inflammatory cells [21,22]. On the other hand, an active remodeling process has been reported to occur in the CAL of acute KD [14,15] which thereafter continues several years after the onset of KD [16]. VEGF can recruit endothelial progenitor cells from the bone marrow into the peripheral circulation [23].…”

Section: Discussionmentioning

confidence: 99%

“…Matrix matalloproteinases (MMP)-2 and -9 were expressed at the CAL in KD, thus suggesting that angiogenesis occurs in the remodeling process of the arterial walls in acute KD vasculitis [15]. Furthermore, an immunohistochemical study demonstrated that intimal proliferation and neoangiogenesis are accompanied by an over-expression of VEGF at the CAL in the late phase of KD [16]. Although the serum levels of VEGF have been reported to increase in the acute phase of KD [17,18], there has so far been no report on the serum levels of ES in this disease.…”

Section: Introductionmentioning

confidence: 99%

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Imbalance in the production between vascular endothelial growth factor and endostatin in Kawasaki disease

Takeshita

Kawamura

Takabayashi

et al. 2005

Clinical and Experimental Immunology

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SummaryTo investigate whether an imbalance exists in the production between angiogenic and antiangiogenic growth factors in patients with Kawasaki disease (KD), we measured the serum levels of vascular endothelial growth factor (VEGF) and endostatin (ES) in 35 patients with KD, 15 patients with acute febrile diseases (disease controls) and 15 healthy children. KD patients had significantly higher VEGF levels and lower ES levels ( P < < < < 0·01) in the acute and subacute phases than the disease control and healthy children. KD patients with coronary artery lesions (CAL, n = = = = 10) had significantly higher VEGF levels and lower ES levels ( P < < < < 0·05) in the subacute and convalescent phases than those without CAL ( n = = = = 25). The ratios of VEGF/ES in sera of KD patients with CAL were significantly higher ( P < < < < 0·05) in the acute and convalescent phases compared to those without CAL. Furthermore, the occurrence of CAL significantly correlated with the VEGF/ES ratio above 10 ¥ ¥ ¥ ¥ 10----3 in the subacute phase of KD (Odds ratio 17·25, P = = = = 0·005). The findings in the present study indicate that an imbalance exists in the production between VEGF and ES in patients with KD while also suggesting that KD patients with a high VEGF/ES ratio have a significantly greater risk of CAL involvement.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Imbalance in the production between vascular endothelial growth factor and endostatin in Kawasaki disease

Takeshita

Kawamura

Takabayashi

et al. 2005

Clinical and Experimental Immunology

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“…Several growth factors are prominently expressed at the inlet and outlet of aneurysms, where they are activated by high shear stress. 57 During the clinical course of Kawasaki disease, vomiting and abdominal pain are seen often. Kurashige and colleagues described the intestinal tract in 31 fatal cases, but in only 3 patients was mesenteric arteritis found.…”

Section: Pathologymentioning

confidence: 99%

“…Aneurysms also may regress to normal internal lumen diameter over time; optimal management of patients with regressed aneurysms is controversial because structural and functional coronary artery abnormalities persist. 57,126,226,235,236 The fol-lowing suggestions for long-term management are based on a consensus of experts and serve as a guide to clinicians until long-term studies and prospective trials facilitate evidencebased practice (evidence level C).…”

Section: Risk Stratificationmentioning

confidence: 99%

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease

Newburger¹,

Takahashi²,

Gerber³

et al. 2004

Circulation

1,613

818

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Background— Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in ∼15% to 25% of untreated children and may lead to ischemic heart disease or sudden death. Methods and Results— A multidisciplinary committee of experts was convened to revise the American Heart Association recommendations for diagnosis, treatment, and long-term management of Kawasaki disease. The writing group proposes a new algorithm to aid clinicians in deciding which children with fever for ≥5 days and ≤4 classic criteria should undergo echocardiography, receive intravenous gamma globulin (IVIG) treatment, or both for Kawasaki disease. The writing group reviews the available data regarding the initial treatment for children with acute Kawasaki disease, as well for those who have persistent or recrudescent fever despite initial therapy with IVIG, including IVIG retreatment and treatment with corticosteroids, tumor necrosis factor-α antagonists, and abciximab. Long-term management of patients with Kawasaki disease is tailored to the degree of coronary involvement; recommendations regarding antiplatelet and anticoagulant therapy, physical activity, follow-up assessment, and the appropriate diagnostic procedures to evaluate cardiac disease are classified according to risk strata. Conclusions— Recommendations for the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. The ultimate decisions for case management must be made by physicians in light of the particular conditions presented by individual patients.

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“…Increased TGF-␤1 protein expression is found in the coronary smooth muscle cells in patients with KD. 34,35 However, although one study 36 found that serum levels of TGF-␤1 were increased in patients with acute KD compared with febrile controls, another study 37 documented that levels were decreased. Therefore, the role that TGF-␤ plays in the pathogenesis of inflammatory arteritis, such as KD, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira

Guignabert

Kim

et al. 2011

The American Journal of Pathology

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Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) ␤ increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-␤ would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-␤ signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-␤ by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-␤ suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-␤, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

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Active Remodeling of the Coronary Arterial Lesions in the Late Phase of Kawasaki Disease

Abstract: Active remodeling of the coronary artery lesions in Kawasaki disease continues in the form of luxuriant intimal proliferation and neoangiogenesis for several years after the onset of the disease. This process is distinct from adult-onset atherosclerosis.

Cited by 173 publications

References 14 publications

Imbalance in the production between vascular endothelial growth factor and endostatin in Kawasaki disease

Imbalance in the production between vascular endothelial growth factor and endostatin in Kawasaki disease

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

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