Takuro Ohno

Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease.

We analyzed the genetic polymorphisms of vascular endothelial growth factor (VEGF) and its receptors [Fms-related tyrosine kinase-1, kinase insert domain receptor (KDR)] in Japanese patients with Kawasaki disease (KD) and normal control subjects to examine whether these genes would contribute to the KD occurrence and/or the development of coronary artery lesion (CAL) in KD. We found that the frequency of G allele of VEGF g.−634 G>C single-nucleotide polymorphism in the promoter region was significantly higher in KD patients with CAL than in those without CAL (p = 0.012) or control subjects (p = 0.021) because of a significantly higher frequency of the GG genotype in KD patients with CAL. In addition, the frequency of the A1 allele with 11 AC repeats of KDR g.+4422(AC)11–14 dinucleotide repeat polymorphism in intron 2 was significantly higher in KD patients with CAL than in those without CAL (p = 0.013) or control subjects (p = 0.040) as a result of a significantly higher frequency of the A1A1 genotype in KD with CAL patients. The multivariate analysis of clinical features and genotypes of the two polymorphisms showed that the A1A1 genotype of KDR g.+4422(AC)11–14 polymorphism was an independent risk factor for the development of CAL with the highest odds ratio among several clinical parameters (odds ratio 6.76; 95% confidence interval 1.05–43.48). Dual luciferase assay demonstrated that the A1 allele with KDR g.+4422(AC)11 repeats showed a weaker silencer function than the A2 allele with 12 AC repeats. These findings suggested that VEGF and its receptor, KDR, genes contributed to the development of CAL in KD patients.

Pulmonary Hypertension in Patients With Congenital Portosystemic Venous Shunt: A Previously Unrecognized Association

BACKGROUND. Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated. METHODS. Nine patients with congenital portosystemic venous shunt were studied from January 1990 through September 2005. RESULTS. Patent ductus venosus was detected in 5 patients, including 3 patients with an absence of the portal vein. The presence of either a gastrorenal or splenorenal shunt was evident in another 4 patients. Six patients had a history of hypergalactosemia with normal enzyme activities, as seen during neonatal screening. Six (66.7%) of the 9 patients were identified to have clinically significant pulmonary arterial hypertension (mean pulmonary artery pressure: 34–79 mm Hg; pulmonary vascular resistances: 5.12–38.07 U). The median age at the onset of pulmonary arterial hypertension was 12 years and 3 months. Histologic studies of lung specimens, which were available in 4 of the 9 patients with congenital portosystemic venous shunt, showed small arterial microthrombotic lesions in 3 patients. This characteristic finding was recognized even in the congenital portosystemic venous shunt patients without PAH. CONCLUSIONS. This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

Genetic Analysis of MMP Gene Polymorphisms in Patients With Kawasaki Disease

Kawasaki disease (KD) is an acute febrile disorder characterized by systemic vasculitis primarily occurring in coronary arteries. Matrix metalloproteinases (MMPs) have been considered to play pathophysiologic roles in the development of coronary artery lesions (CALs); therefore, an evaluation of the genetic contributions of the MMP genes to the development of CALs in KD patients would be beneficial for the prediction of CAL formation. We focused on the known functional single nucleotide polymorphisms (SNPs) in the MMP genes (MMP-2-735C>T, MMP-3-1612 5A/6A, MMP-9-1562C>T, MMP-12-82A>G, and MMP-13-77A>G) and performed the association study between these SNPs and CAL formation in KD. The study population consisted of 44 KD patients with CALs and 92 without CALs and 175 healthy controls. As a result, allele and genotype frequencies of MMP-13-77A>G showed significant differences between KD patients with CALs and without CALs (p = 0.00989 and p = 0.00551, respectively). The estimated frequencies of the G-C haplotype in the MMP-13 gene promoter were significantly lower in KD patients with CALs than in those without CALs. There was no association between other MMP genes and CAL formation. In conclusion, the genetic evaluation by association study demonstrated that the MMP-13 gene, at least in part, contributed to the development of CALs in KD.

Th1 and Th2 cytokine production is suppressed at the level of transcriptional regulation in Kawasaki disease

To clarify the functional state of T cells in Kawasaki disease, we analysed mRNA expression levels of Th1/Th2 cytokines (IFN‐γ and IL‐4) along with Th1/Th2‐inducing transcription factors, T‐bet and GATA‐3, which play pivotal roles in the development of Th1 and Th2 cells, respectively. By real‐time PCR, IFN‐γ mRNA levels in peripheral blood mononuclear cells (PBMNC) were significantly decreased in Kawasaki disease patients compared with those with measles, and tended to be lower than those in healthy controls. T‐bet mRNA levels were significantly decreased in patients with Kawasaki disease compared with healthy controls. In addition, IL‐4 and GATA‐3 mRNA levels were significantly decreased in Kawasaki disease compared with healthy controls. Regulatory cytokine mRNA levels (TGF‐β and IL‐10) were also decreased in Kawasaki disease. The mRNA levels of IFN‐γ showed a significant positive correlation with those of T‐bet in Kawasaki disease. These results suggest that the suppressed function of Th1 and Th2, associated with the suppression of both T‐bet and GATA‐3 gene expression, may be one of the immunological characteristics of Kawasaki disease.

Serum vascular endothelial growth factor: a new predictive indicator for the occurrence of coronary artery lesions in Kawasaki disease.

Abstract We investigated serum vascular endothelial growth factor (SVEGF) levels in Kawasaki disease and determined whether these levels had any association with the development of coronary artery lesions. We measured SVEGF levels in 66 patients with Kawasaki disease, 18 patients with active infections and 18 afebrile controls. SVEGF levels of patients in the acute phase of Kawasaki disease (0.0–2003.6 pg/ml, median 59.87 pg/ml) were significantly higher than those of patients with active infections (0.0–45.2 pg/ml, median 8.10 pg/ml; P < 0.05) or afebrile controls (0.0–49.8 pg/ml, median 7.75 pg/ml; P < 0.05) and decreased to undetectable or low levels in the recovery phase (n=31, acute phase: 0.0–2003.6 pg/ml, median 62.50 pg/ml versus recovery phase: 0.0–146.5 pg/ml, median 26.90 pg/ml; P=0.0007) of the disease. There existed a positive correlation between SVEGF levels and serum C-reactive protein concentrations in the acute phase of Kawasaki disease (rs=0.347, P=0.0051). In addition, SVEGF level and duration of fever were found to be major risk factors for the occurrence of coronary artery lesions by univariate (P=0.012 and P=0.003, respectively) and multivariate (P=0.037, OR 6.16 and P=0.0059, OR 7.59, respectively) analyses. Conclusion Serum vascular endothelial growth factor level, in combination with persistence of fever, could be a powerful predictor for the development of coronary aneurysms.

Long-term prospective study on the natural history of Wolff-Parkinson-White syndrome detected during a heart screening program at school

In the period 1985 to 1993, a total of 802 school‐aged children (284 first‐graders and 518 seventh‐graders) were referred to our hospital for further evaluation of electrocardiographic abnormalities. Among them, 57 (male 24 and female 33) children were confirmed as having Wolff‐Parkinson‐White (WPW) syndrome based on the findings of 12‐lead surface electrocardiograms (ECG). According to Lindsays criteria, the locations of the accessory pathways were as follows: Left‐lateral in 10 (18%), left‐posterior in 2 (4%), right‐free‐wall in 28 (49%), anterior‐septum in 13 (23%) and posterior‐septum in 3 (5%). One 12‐y‐old girl had multiple accessory pathways. Six patients had associated diseases: Ebsteins anomaly in 4, epilepsy in 1 and mental retardation with scoliosis in 1. Follow‐up periods ranged from 2.0 to 13.0 y (mean SD: 8.0 ± 3.3 y) for 23 first‐graders with WPW syndrome, and from 2.0 to 13.0 y (mean SD: 7.3 ± 4.2 y) for 34 seventh‐graders, respectively. Initially, 5 children had at least one episode of supraventricular tachycardia (SVT) by history and 6 children developed SVT during the follow‐up. One girl with multiple accessory pathways and recurrent SVT required long‐term drug therapy.

Serum hepatocyte growth factor combined with vascular endothelial growth factor as a predictive indicator for the occurrence of coronary artery lesions in Kawasaki disease

Abstract. We investigated the possible use of serum hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels as a predictive indicator for the occurrence of coronary artery lesions (CAL) in Kawasaki disease (KD). Serum HGF and VEGF levels were measured by enzyme-linked immunosorbent assay in 41 patients with KD and 25 afebrile controls. Serum HGF levels of patients in the acute phase of KD were significantly higher than those of afebrile controls (Pc<0.05) and decreased to lower levels during recovery (P<0.0001). Univariate analysis showed significant correlations between occurrence of CAL and five variables: duration of fever (P=0.018), serum C-reactive protein concentration (P=0.024), albumin concentration (P=0.009), serum VEGF level (P=0.009) and serum HGF level (P=0.035). Furthermore, multivariate analysis revealed that serum HGF and VEGF levels and presence of oedema were major risk factors for the occurrence of CAL. For prediction of the development of CAL, we established a new risk classification system with these three variables, which showed a sensitivity of 100% and a specificity of 94.4%. Conclusion: these data show that hepatocyte growth factor, together with vascular endothelial growth factor, might play an important role in the pathophysiology of Kawasaki disease and their serum levels could be a powerful predictor for the development of coronary artery lesions.

Outcomes of cardiac surgery in trisomy 18 patients.

OBJECTIVE The objective was to clarify the outcomes of cardiac surgery in trisomy 18 patients. PATIENTS AND METHODS We analysed 34 consecutive trisomy 18 patients, of whom 21 were males, with cardiac complications. They were divided into patients who underwent cardiac surgery and those who were conservatively treated. We compared rates of survival and discharge alive between two groups. RESULTS The surgery group included nine patients, with six males, who underwent cardiac surgery - intracardiac repair in three patients, pulmonary arterial banding in five patients, and ligation of the ductus in one patient - at median age of 2.2 months, ranging from 0.5 to 9.8, and with median weight of 2.6 kilograms, ranging from 1.5 to 3.2. Cardiac surgery and pre-operative assisted ventilation were hazardous factors leading to death. In the surgery group, cumulative survival rates at 1 month, 6 months, 12 months, and 24 months were 63%, 38%, 25%, and 22%, respectively, compared with 51%, 26%, 9%, and 9% in the conservative group. There was a significant difference (p = 0.002). The cumulative rates of discharge alive at 1 month, 3 months, and 6 months were 0%, 12%, and 65% in the surgery group, which did not differ from the conservative group (p = 0.80). CONCLUSIONS Cardiac surgery contributed to increased survival rate but not the rate of discharge alive in trisomy 18 patients. Cardiac surgery could not prevent all the trisomy 18 patients from death. The indication of cardiac surgery should be carefully individualised to improve the quality of life in trisomy 18 patients and concerned surrounding people.

Auxiliary Partial Orthotopic Living Donor Liver Transplantation for a Child with Congenital Absence of the Portal Vein

Congenital absence of the portal vein (CAPV) is a rare malformation of the mesenteric vasculature in which visceral venous blood bypasses the liver, completely draining into the systemic circulation through a congenital porto‐systemic shunt. Liver transplantation has rarely been indicated for patients with this disease. We present a child with CAPV who was managed successfully by living donor auxiliary partial orthotopic liver transplantation (APOLT), while preserving the right lobe of the native liver. In conclusion, APOLT for patients with CAPV is a feasible and ideal procedure because portal vein (PV) diversion is not necessary. Liver Transpl 12:845–849, 2006.

Maturational alterations of peripheral T cell subsets and cytokine gene expression in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real‐time polymerase chain reaction (PCR). CD3+, CD4+, T cell receptor (TCR)αβ+ or CD8αα+ cell counts were lower, and CD56+ cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3+ or CD4+ cell counts was slower in patients than in controls. The proportion of CD8αα+ cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of Vα24+ cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8αα+ cells was observed only in patients, and that with Vα24+ cells was seen only in controls. No gene expression levels of interferon (IFN)‐γ, interleukin (IL)‐10, transforming growth factor (TGF)‐β, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T‐lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome.