Toshiyuki Itoi

Effects of HMG-CoA reductase inhibitors on continuous post-inflammatory vascular remodeling late after Kawasaki disease

BACKGROUND In Kawasaki disease (KD), it has been clinically and experimentally reported that post-inflammatory vascular remodeling would induce the development of arteriosclerosis or early onset of atherosclerosis in the future. The effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on continuous vascular remodeling late after Kawasaki disease were clinically evaluated. PATIENTS AND METHODS We enrolled and treated a total of 11 KD patients (age range, 7-25 years) with fluvastatin (0.5-0.7 mg/kg/day) for 12 months. All of them had significant coronary aneurysmal or stenotic lesions and more than 3 of the following 5 abnormal findings: reduced %flow-mediated dilatation (%FMD), reduced urinary NOx, elevated high-sensitivity C-reactive protein (hs-CRP), reduced urinary 8-isoprostane, and elevated brachial-ankle pulse wave velocity (baPWV; control, ≤1400 cm/s). RESULTS A statistically significant improvement was observed in each biomarker after fluvastatin treatment: %FMD, from 9.29% (3.41)% to 10.55% (3.27)% (p=0.003) after 3 months; NOx/creatinine (cre), from 1.16 (0.54) µmol/mg cre to 1.30 (0.50) µmol/mg cre (p=0.038) after 12 months; baPWV, from 1175.4 (277.3) cm/s to 1031.8 (155.6) cm/s (p=0.009) after 3 months; hs-CRP, from 0.073 (0.035) mg/dl to 0.028 (0.014) mg/dl (p=0.0002) after 3 months; and 8-iso/cre, from 751.8 (241.8) pg/mg cre to 660.0 (198.5) pg/mg cre (p=0.018) after 3 months. No adverse events were clinically observed in the patients. CONCLUSIONS The results of this study suggested that HMG-CoA reductase inhibitors are useful as an alternative therapeutic strategy for stabilizing continuous post-inflammatory vascular remodeling that results in the development of arteriosclerosis late after KD or early onset of atherosclerosis in the future.

Renal function and cardiac angiography.

Objective: To study the effect of non-ionic contrast medium on renal function in children with cardiovascular disease.Methods: Analysis of renal function in 98 children with cardiovascular disease before and after the use of lopamidol, lohexol, and loversol was done for angiography. Serum creatinine (s-Cre), urinary N-acetyl-beta-D-glucosaminase (u-NAG), urinary beta 2-microglobulin (u-BMG), and urinary alpha 1-microglobulin (u-AMG) levels were evaluated.Results: Although s-Cre levels remained unchanged, u-NAG/Cre, u-AMG/Cre and u-BMG/Cre significantly increased 12 hours after angiography. Levels of u-NAG/Cre, u-BMG/Cre, and u-AMG/Cre after angiography were significantly higher in neonates and infants (age<12-Months, n=32) than in children (age>1-year, n=61), in patients with more than 5 ml/kg of contrast medium (n=25) than in those with less than 5 ml/kg (n=70) and in cyanotic patients (n=13) than in non-cyanotic (n=80) patients.Conclusion: Transient renal tubular dysfunction occurred in all of these three non-ionic contrast mediums. Although renal tubular function was intact on a long-term basis, one should be careful of contrast medium-induced nephropathy, especially in neonates and infants, in patients receiving more than 5 ml/kg of contrast mediums in total, and in patients with cyanotic heart disease in using non-ionic contrast mediums.

The role of apelin on the alleviative effect of Angiotensin receptor blocker in unilateral ureteral obstruction-induced renal fibrosis.

Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1). The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO) model. Results: We obtained the following results: (1) At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS) in the UUO kidney were increased compared to those in the nonobstructed kidney. (2) AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3) Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4) Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

Impaired transient elevation of blood hemoglobin in response to acute hypoxia in neonates with asplenia

Background: It has been shown that acute hypoxia induces the transient elevation of blood hemoglobin concentration ([Hb]) as a consequence of sympathetic‐mediated splenic contraction to maintain the supply of oxygen, and splenectomy abolishes this phenomenon. The purpose of the present paper was to determine, retrospectively, whether the ability of transient elevation of [Hb] against acute hypoxia would be impaired in neonates with asplenia.

Recovery from Fontan circulation failure by application of continuous negative extrathoracic pressure

A 2-year-old girl developed lethal circulatory failure, general edema, and hepatic dysfunction in an acute phase after total cavopulmonary connection, a Fontan-type operation. Application of continuous negative extrathoracic pressure (CNEP) with a cuirass ventilator at −4 cmH2O under spontaneous respiration dramatically improved hemodynamics, with systolic arterial pressure increasing from 82 mmHg to 90 mmHg, and central venous pressure decreasing from 15 mmHg to 13 mmHg; also, urine output increased, from 1.6 ml·kg−1·h−1 to 6.4 ml·kg−1·h−1. Improvements in hepatic function and fluid retention (reduction of pleural fluid and ascites) were also observed. The patient was successfully weaned from CNEP after 5 days. CNEP is an easily applicable, noninvasive tool to reduce pulmonary impedance, and is specifically useful to improve hemodynamics in patients after a Fontan-type operation. Our result suggests that CNEP may represent a first-line option to save patients from critical circulatory failure after a Fontan-type operation.

Abnormal coronary flow reserve in a 13-year-old girl with an absent left circumflex coronary artery.

Abstract. We measured the coronary flow reserve in a 13-year-old girl with the rare anomaly of an absent left circumflex coronary artery. Although the coronary flow volume of the right coronary artery was at the same level as that of the left anterior descending coronary artery, the coronary flow reserve of the patients right coronary artery was depressed without stenotic lesion, and it was less than the level of −2 standard deviation (SD) of the right coronary artery preponderance cases.

Coronary sinus cannulation via the femoral vein

SummaryCannulation of the coronary sinus has been usually accomplished by advancing a catheter through the brachial vein, subclavian vein, or internal jugular vein by venous cutdown or a sheath method. We here describe a technique for cannulation into the coronary sinus through the femoral vein by using a modified catheter. This catheter was easily inserted into the coronary sinus in all of 40 consecutive patients in whom it was attempted.

Tolerance to ischemia reperfusion injury in a congenital heart disease model

Open heart surgery‐associated ischemia/reperfusion (I/R) injury affects postoperative outcome, and a leading cause of this is lipid peroxidation. Congenital heart disease (CHD) patients, however, are less sensitive to I/R injury. Although little is known about the underlying molecular mechanisms, CHD‐associated hypoxia alters the polyunsaturated fatty acid (PUFA) composition of membranes, which are the preferential targets for reactive oxygen species (ROS) generated during I/R. Here, using an animal model, we investigated the molecular mechanisms underlying I/R tolerance in CHD.

A case of Fabry nephropathy with histological features of oligonephropathy

Newborn screening studies indicate the expected high incidence of later-onset Fabry disease with silent Fabry nephropathy while, with recent improved clinical care of premature infants, children with congenital oligonephropathy caused by premature embryonal development of the kidney are thought to be increasing. However, the coexistence of Fabry nephropathy and oligonephropathy has not been reported previously. We present the case of a 13-year-old boy who was diagnosed with Fabry nephropathy accompanied with histological features of oligonephropathy. He was born as a preterm baby, and a renal biopsy was performed because of mild renal dysfunction and mild proteinuria. He had neither characteristic early symptoms nor a family history of Fabry disease. Histologic findings demonstrated diffuse global enlargement and foamy change of podocytes with markedly decreased number and enlargement of the glomeruli. Both his plasma and leukocyte α-galactosidase A (GLA) activities were markedly decreased, and the plasma globotriaosylsphingosine and urine globotriaosylceramide levels were increased. Gene analysis revealed a missense mutation, R112H, in the GLA gene, which had been reported in the later-onset phenotype of Fabry patients. He is now under treatment with enzyme replacement therapy and an angiotensin-converting enzyme inhibitor. Conclusion: This case indicated the possible co-occurrence of Fabry nephropathy and oligonephropathy. For early diagnosis and timely management, careful examinations for proteinuria and renal function, in addition to establishing an effective screening system for Fabry disease, will be necessary.

Successful radiofrequency catheter ablation for ventricular tachycardia of a 2.9 kg infant with Ebstein's anomaly

A 39-day-old female infant with Ebsteins anomaly, pulmonary atresia, atrial septal defect, and patent ductus arteriosus developed repetitive critical ventricular tachycardia (VT) ranging from 200 to 240 bpm. We assumed the focal VT originated from the right ventricle (RV) from the electrocardiographic features. Pharmacological …