Decreased serum Annexin A1 levels in Kawasaki disease with coronary artery aneurysm.

BACKGROUND: Kawasaki disease (KD) is an acute and systemic vasculitis whose etiology remains unclear. The most crucial complication is the formation of coronary artery aneurysm (CAA). Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases. This study sought to investigate the serum ANXA1 levels in KD patients and further explore the relationship between ANXA1 and CAA, as well as additional clinical parameters. METHODS: Serum samples were collected from 95 KD patients and 39 healthy controls (HCs). KD patients were further divided into two groups: KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs). Serum levels of ANXA1 and interleukin-6 (IL-6) were determined using enzyme-linked immunosorbent assays. RESULTS: Serum ANXA1 levels in the KD group were significantly lower than in the HC group. In particular, serum ANXA1 levels were substantially lower in the KD-CAA groups. Moreover, serum ANXA1 levels were positively correlated with N%, C-reactive protein (CRP), and IL-6 but negatively correlated with L% in the KD group. Positive correlations between serum ANXA1 levels and erythrocyte sedimentation rate (ESR), IL-6, and D-dimer (DD) were observed in the KD-CAA group. CONCLUSIONS: ANXA1 may be involved in the development of KD, and downregulation of ANXA1 may lead to the hypercoagulability seen in KD. IMPACT: For the first time, it was demonstrated that serum ANXA1 levels were significantly decreased in Kawasaki disease with coronary artery aneurysms. ANXA1 might be involved in the acute phase of Kawasaki disease. Low serum concentrations of ANXA1 might lead to the hypercoagulability stage in Kawasaki disease. ANXA1 might be a potential therapeutic target for patients with Kawasaki disease.

Spontaneous coronary artery dissection in puerperium.

Spontaneous coronary artery dissection in puerperium is uncommon and most often occurs in the third trimester of pregnancy and in the early postpartum period. Two weeks after delivery, a 41-year-old woman presented with typical retrosternal chest pain and inverted T-waves in leads II, V5 and V6, and Q-waves in aVR. Her peak troponin I level was 16.39 µgcL(-1) Coronary angiography showed left main spiral dissection extending to the mid left anterior descending artery and involving the first diagonal branch. Urgent coronary artery bypass grafting was performed successfully. The mechanism and approach are discussed.

Immunoglobulin G4-related multiple cardiovascular lesions successfully treated with a combination of open surgery and corticosteroid therapy.

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.

Acute pericardial effusion representing the TNF-α-mediated severe inflammation but not the coronary artery outcome of Kawasaki disease.

OBJECTIVES: To establish the optimal inflammation control of Kawasaki disease (KD), we investigated the clinical and pathophysiological basis of pericardial effusion (PE) during the acute phase of KD. METHOD: Clinical and laboratory features of Japanese KD children with PE (PE group: n = 9) and without PE (non-PE group: n = 89) were studied retrospectively by using the medical records. Serum levels of soluble tumour necrosis factor receptor 1 (sTNFR1), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assays (ELISAs). RESULTS: PE group patients had coronary artery lesions (CALs) more frequently than non-PE group patients during the acute phase of KD (33% vs. 5.6%, p = 0.024). PE patients also showed lower levels of haemoglobin (p < 0.01) and serum albumin (p < 0.01) and higher platelet counts (p = 0.013) than non-PE patients. The proportion of neurological symptoms, but not other manifestations, in the PE group was higher than in the non-PE group (p = 0.022). All patients survived free from coronary artery aneurisms. Serum levels of sTNFR1, but not the other cytokines, in the PE group were higher than those in the non-PE group (p < 0.001). The sTNFR1 levels correlated positively with C-reactive protein (CRP) (r = 0.30, p = 0.019) or total bilirubin (r = 0.40, p < 0.01) levels. CONCLUSIONS: Acute PE in KD patients indicated the severity of TNF-mediated vascular inflammation and concurrent CALs. According to the progression, these patients might need more targeted therapy of anti-inflammation for a better coronary outcome.

Coronary aneurysms in a child: an unusual presentation of pseudovasculitis.

Abnormalities of the coronary arteries in children are rare and Kawasaki disease is the most common cause of acquired coronary disease in a paediatric population. We report a case of a female child with coronary artery aneurysms and convulsions, who was diagnosed with Kawasaki disease. Due to systemic arterial hypertension and persistence of high inflammatory markers after treatment with high dose glucocorticoid and intravenous immunoglobulin, further investigation was performed and revealed a pheochromocytoma. Surgical removal led to normalization of blood pressure and laboratory parameters. Periodic echocardiography studies revealed progressive reduction of coronary aneurysms, with complete normalisation after 8 months. This is the first case described of coronary aneurysms presenting as a pseudovasculitis syndrome associated with pheochromocytoma.

A case of multiple giant coronary aneurysms and abdominal aortic aneurysm coexisting with IgG4-related disease.

IgG4-related disease (IgG4RD) is a unique systemic lymphoproliferative disorder characterized by elevated serum IgG4 levels and IgG4-producing plasma cell expansion in the affected tissues, which are accompanied by fibrotic or sclerotic changes. Vascular lesions may also be a part of IgG4RD as a number of case reports have discussed inflammatory abdominal aortic aneurysms associated with IgG4RD, but coronary artery lesions seem to be rare complications of IgG4RD. A 71-year-old man suffered from multiple giant coronary aneurysms and an abdominal aortic aneurysm with concurrent pancreatic, gall bladder, bile duct, and salivary gland lesions resulting from IgG4RD. The present observations suggest that coronary aneurysms may also develop as a consequence of this disease.

Significant coronary artery disease associated with coronary artery aneurysm and elevation of prostate-specific antigen during acute myocardial infarction.

Coronary artery aneurysms are defined as coronary dilatations which exceed the diameter of normal adjacent segments by 1.5 times. Although more commonly associated with atherosclerosis, a variety of other acquired (eg, inflammatory, infectious, iatrogenic) or congenital causes have been identified that lead to impaired vessel media. A number of complications have been reported to occur during the course of the disease including thrombosis and distal embolization, myocardial ischemia and/or infarction, dissection, vasospasm, calcification, fistulization and rupture. Other complications relate to the size of the aneurysm and compression of adjacent structures. Prostate-specific antigen (PSA) is an established marker for detection of prostate cancer. Elevation of prostate-specific antigen as well as its diminution during acute myocardial infarction has also been reported. It seems that when elevation of prostate-specific antigen occurs during acute myocardial infarction, coronary lesions are frequent and often more severe than when diminution of prostate-specific antigen occurs. PSA has been identified as a member of the human kallikrein family of serine proteases. In recent years, numerous observations have suggested that the activity of the kallikrein-kinin system is related to inflammation and to cardiovascular diseases. We present a case of elevation of serum PSA concentration during acute myocardial infarction in a 64-year-old Italian man with significant coronary artery disease and coronary artery aneurysm. Also this case confirms previous findings and extends the evaluation of PSA during acute myocardial infarction. It confirms a possible new intriguing scenario of the role of the prostate-specific antigen in acute myocardial infarction.

Impairment of angiogenic activity in the serum from patients with coronary aneurysms due to Kawasaki disease.

BACKGROUND: The inflammatory mediators play an important role in the progression of coronary vasculitis in Kawasaki disease (KD), but effects of KD serum including inflammatory mediators on endothelial cells remain unknown. We hypothesized that serum activity to stimulate in vitro human umbilical vein endothelial cells (HUVEC) tube formation might be impaired in KD. METHODS AND RESULTS: Serum from patients with coronary aneurysms was less active in stimulating HUVEC tube formation than serum from patients without coronary aneurysms or febrile controls. In patients with coronary aneurysms, the reduction in the serum angiogenic activity was documented already before KD treatment (p=0.03 vs healthy controls, p=0.08 vs febrile controls) and enhanced after intravenous immune globulin plus aspirin (p<0.001 vs healthy controls, p=0.002 vs febrile controls); both drugs did not affect the assay studied. This reduction was greater in patients who later developed giant aneurysms >8 mm compared with those who developed small to moderate aneurysms (p=0.01). The reduced serum angiogenic activity was partly caused by the reduction in the serum activity of stimulating HUVEC proliferation. CONCLUSIONS: Serum activity to stimulate HUVEC tube formation was impaired in KD patients who later developed larger coronary aneurysms, which may be associated with the severity of vascular injury.

Identifying cardiovascular risk factors in a patient population with coronary artery ectasia.

Coronary artery ectasia (CAE) is frequently considered as a form of coronary artery disease. Cardiovascular risk factors were determined in a patient population with CAE. The 51 patients with isolated CAE (group 1), 61 patients with CAE coexisting with significant coronary stenosis (group 2), and 62 subjects with significant coronary stenosis (group 3) were included in the study, and the distribution of cardiovascular risk factors was compared. Thirty of 51 patients with isolated CAE had presented with typical angina pectoris, 8 patients with unstable angina pectoris, and 13 patients had atypical chest pain or palpitation. The 21 of 51 patients with isolated CAE had definitive positive treadmill exercise test results. Positive family history was similar in each group. The history of smoking was similar in group 1 and group 2 but higher than group 3. Frequency of hypertension was similar in group 1 and group 2 but higher than that in group 3. Frequency of diabetes mellitus was similar in group 1 and group 2 but lower than group 3. Plasma lipid levels and the number of patients with lipid disturbances were also similar in each group. In addition, C-reactive protein (CRP) levels were above the normal limits and there was no difference among groups with respect to plasma CRP levels. CAE appears to be associated with traditional cardiovascular risk factors such as hypertension, smoking, and hyperlipidemia. In addition, elevated CRP level in patients with CAE may suggest the role of inflammatory process in development of CAE.

New insights into molecular mechanisms of diffuse coronary ectasiae: a possible role for VEGF.

BACKGROUND: Diffuse coronary artery ectasiae (DCE) are occasionally found at necropsy or at angiography. Pathogenetic mechanisms of DCE are still poorly known. Matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and vascular endothelial growth factor (VEGF) are involved in vascular remodeling and may play a role in DCE. METHODS: A total of 1280 consecutive coronary angiograms performed in a single institution in 1 year were screened. DCE were found in 15 patients. Diagnosis at hospital admission was acute coronary syndromes in all of them. Two patients died during initial admission and 1 refused blood sampling; the remaining 12 patients were enrolled in the study. No patient with DCE exhibited coronary stenoses. Plasma levels of VEGF, MMP-2, TIMP-1, TIMP-2 and C-reactive protein (CRP) were measured in these 12 patients 12 months after discharge during a silent clinical phase, in 12 age- and sex-matched patients with stable angina (SA) and coronary artery disease, and in 12 age- and sex-matched patients with normal coronary arteries (NCA). RESULTS: VEGF levels were higher in patients with DCE than in SA or NCA (151.6 pg/ml [36.2-252.9] vs. 66.6 pg/ml [36.4-93.3] and 54.8 pg/ml [14.5-87.1], respectively, p = 0.012]. TIMP-2 levels were lower in DCE and SA than in NCA (5.9 ng/ml [0-33.6] and 5.0 [0-17.4] vs. 139.3 ng/ml [114.4-237.4], respectively, p < 0.001). TIMP-1 and MMP-2 plasma levels were similar in all groups (p = NS), and CRP levels were within normal limits (< 3 mg/L) in most patients, irrespective of their coronary anatomy (75% for DCE, 66% for SA, and 84% for NCA [p = NS]). CONCLUSIONS: Symptomatic patients with DCE typically present with an acute coronary syndrome and exhibit lack of obstructive stenosis at angiography, decreased plasma levels of TIMP-2 and raised plasma levels of VEGF. The simultaneous occurrence of reduced MMPs inhibition and increased angiogenetic activity suggests an accelerated and persistent extracellular matrix remodeling process favouring arterial remodeling and aneurysms formation which is likely to enhance the risk of thrombosis because of low shear stress.

Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease.

Several compelling lines of evidence suggest an important influence of genetic variation in susceptibility to Kawasaki disease (KD), an acute vasculitis that causes coronary artery aneurysms in children. We performed a family-based genotyping study to test for association between KD and 58 genes involved in cardiovascular disease and inflammation. By analysis of a cohort of 209 KD trios using the transmission disequilibrium test, we documented the asymmetric transmission of five alleles including the interleukin-4 (IL-4) C(-589)T allele (P=0.03). Asymmetric transmission of the IL-4 C(-589)T was replicated in a second, independent cohort of 60 trios (P=0.05, combined P=0.002). Haplotypes of alleles in IL-4, colony-stimulating factor 2 (CSF2), IL-13, and transcription factor 7 (TCF7), all located in the interleukin gene cluster on 5q31, were also asymmetrically transmitted. The reported associations of KD with atopic dermatitis and allergy, elevated serum IgE levels, eosinophilia, and increased circulating numbers of monocyte/macrophages expressing the low-affinity IgE receptor (FCepsilonR2) may be related to effects of IL-4. Thus, the largest family-based genotyping study of KD patients to date suggests that genetic variation in the IL-4 gene, or regions linked to IL-4, plays an important role in KD pathogenesis and disease susceptibility.

Elevated levels of high-sensitivity C-reactive protein and serum amyloid-A late after Kawasaki disease: association between inflammation and late coronary sequelae in Kawasaki disease.

BACKGROUND: Coronary sequelae that persist after Kawasaki disease (KD) have been associated with obstructive changes of the lesions and coronary vascular events in adolescents and young adults. However, little is known about the association between sequelae late after KD and inflammatory markers, which are potential mediators and markers for atherogenesis. METHODS AND RESULTS: Cross-sectional study was performed to test the hypothesis that coronary sequelae are associated with elevated levels of inflammatory markers in patients late after KD (mean time interval after the onset, 10 years, 10 months). Levels of high-sensitivity C-reactive protein (CRP), serum amyloid-A (SAA), interleukin-6, and soluble intercellular adhesion molecule-1 were measured in the 4 groups (n=80): the referent group (n=15) and KD subgroups with normal coronary arteries from the onset (n=27); with regressed aneurysms (n=18); and with coronary artery lesions, such as persistent aneurysms, stenosis, and occlusion (n=20). CRP levels were significantly elevated in a KD subgroup with coronary artery lesions compared with the referent or other KD subgroups, as analyzed by ANOVA and ANCOVA after adjustment for a confounding factor body mass index. Levels of CRP, SAA, and interleukin-6 were positively correlated. Stepwise regression and logistic regression analyses support the association between the persistence of coronary artery lesions and the levels of CRP and SAA. CONCLUSIONS: Results demonstrate that the persistence of coronary lesions late after KD was independently associated with levels of CRP and SAA, suggesting that inflammation may be a novel functional aspect of coronary artery diseases late after KD.

Assessment of coronary function in children with a history of Kawasaki disease using (15)O-water positron emission tomography.

BACKGROUND: Coronary abnormalities after Kawasaki disease (KD) may be associated with endothelial dysfunction due to intimal hypertrophy. The purpose of this study was to evaluate myocardial flow reserve (MFR) and endothelial function in regressed aneurysmal regions after KD. Methods and Results- Subjects were 12 patients aged 16.0+/-2.6 years who suffered from KD at 1.7+/-1.5 years and 12 normal subjects aged 26.5+/-3.4 years. MFR and endothelial function were estimated, respectively, by changes in myocardial blood flow (MBF) during ATP infusion and by that during cold pressor test using (15)O-water positron emission tomography. Data from 24 regressed aneurysmal regions were compared with those from the corresponding regions (n=36) in the control group. Although the MBF at rest in the regressed aneurysmal regions was similar to that in controls, the MBF at a hyperemic state induced by ATP infusion in the regressed aneurysmal regions was significantly lower than that in the control regions. Therefore, the MFR in regressed aneurysmal regions was significantly lower than that in controls (3.53+/-0.95 versus 4.60+/-1.14; P<0.05). MBF at rest and during the cold pressor test did not change in the control regions, but it was significantly reduced in regressed aneurysmal regions. The ratio of MBF during the cold pressor test to MBF at rest was significantly lower in regressed aneurysmal regions than in control regions (0.67+/-0.15 versus 1.00+/-0.15; P<0.05). CONCLUSIONS: MFR and endothelial function are often impaired in regressed aneurysmal regions after KD, and tomography enables the noninvasive evaluation of coronary function.

Immediate stent implantation versus conventional techniques for the treatment of abrupt vessel closure or symptomatic dissections after coronary balloon angioplasty.

BACKGROUND: Coronary stenting was initially designed to treat a bailout scenario. Prospective randomized trials comparing stent implantation with standard techniques, including emergency coronary artery bypass grafting, are lacking. The aim of this trial was to test the superiority of immediate stent implantation compared with standard techniques for the treatment of abrupt or threatening closure after coronary balloon angioplasty. METHODS: In a prospective trial, 100 patients with abrupt vessel closure or symptomatic dissections causing objective signs of ischemia were randomly assigned to treatment with immediate placement of stents (n = 51) versus standard techniques such as prolonged dilatation or emergency bypass surgery (n = 49). The primary end point was the achievement of successful stabilization not requiring crossover to the other study group. Secondary end points included event-free survival and restenosis. RESULTS: Successful stabilization was achieved in 94% of patients in the stent group compared with 78% of patients in the standard treatment group (P =.038). Two patients died in each group, and there was a trend toward a higher incidence of myocardial infarction (16% vs 8%; P =.163) and a significantly increased creatine phosphokinase level (245 IU/L [95% confidence interval, 217-265 IU/L] vs 179 IU/L [confidence interval 140-212 IU/L]; P =.0002) in the standard treatment group. Event-free survival after 250 days was 72% in the stent group compared with 29% in the standard treatment group (P =.001). The angiographic restenosis rate was 30% in the stent group versus 59% in the standard treatment group (P =.01). CONCLUSIONS: Immediate stenting, if technically feasible, shows superior short- and long-term results compared with standard treatment options.

Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease.

To determine the role of cytokines in Kawasaki disease, serial measurements of serum cytokine levels were done in 60 patients treated solely with aspirin. Coronary artery aneurysms later developed in 12 of them. The results suggest that elevated serum interleukin-6 and interleukin-8 levels during the first week of illness may be associated with a higher risk of coronary aneurysm formation.

Peripheral blood monocyte/macrophages and serum tumor necrosis factor in Kawasaki disease.

We analyzed the populations of peripheral blood monocyte/macrophages in 27 patients using a fluorescence-activated cell sorter, and investigated the possibility, in another 30 patients, that tumor necrosis factor (TNF) might be detectable in serum during the acute phase of Kawasaki disease (KD). Percentages of peripheral blood monocyte/macrophages among mononuclear cells and serum TNF levels were both seen to increase during the acute phase of the illness in patients with KD. The percentage of TNF positive cases in KD patients with coronary involvement was higher than that of patients without coronary involvement. These results suggest the possibility that immunological activation, accompanied by the secretion of TNF from monocyte/macrophages, is an important predisposing condition for the exacerbation of vascular damage in KD.