Takashi Higaki

Nitric Oxide and Reactive Oxygen Species in the Pathogenesis of Preeclampsia

Preeclampsia (PE) is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of nitric oxide (NO) and tissue damage caused by increased levels of reactive oxygen species (ROS). Furthermore, superoxide (O2−) rapidly inactivates NO and forms peroxynitrite (ONOO−). It is known that ONOO− accumulates in the placental tissues and injures the placental function in PE. In addition, ROS could stimulate platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. The disorders could lead to the reduction of oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the other hand, several antioxidants scavenge ROS and protect tissues against oxidative damage. Placental antioxidants including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) protect the vasculature from ROS and maintain the vascular function. However, placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria. Oxidative stress is defined as an imbalance between ROS and antioxidant activity. This review provides new insights about roles of oxidative stress in the pathophysiology of PE.

ACE2 deficiency induced perivascular fibrosis and cardiac hypertrophy during postnatal development in mice

In order to investigate the role of angiotensin-converting enzyme 2 (ACE2) in cardiac development, we examined the effects of ACE2 deficiency on postnatal development of the heart using ACE2-knockout (ACE2KO) mice. Heart samples of wild type (WT; C57BL/6J) mice and ACE2KO mice were taken at 1, 4, and 10 weeks of age. In WT mice, expression of ACE2 mRNA increased from 1 week to 10 weeks. A similar increase was observed in immunostaining of ACE2 in the heart, in which ACE2 was strongly expressed in coronary arteries. Compared with WT mice, heart weight was greater in ACE2KO mice at 4 weeks, and coronary artery thickening and perivascular fibrosis were also already enhanced from 4 weeks. Consistent with the increase of fibrosis, cardiac expression of collagen and TIMP was higher, and expression of MMP was lower in ACE2KO mice at 4 weeks. In addition, TGF-β mRNA was also higher, and lower expression of PPARγ mRNA was observed at 4 weeks in ACE2KO mice. These results suggest that ACE2 plays an important role in postnatal development of the heart, and that lack of ACE2 enhances coronary artery remodeling with an increase in perivascular fibrosis and cardiac hypertrophy already around the weaning period.

Novel dominant-negative mutant of GATA3 in HDR syndrome.

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G> C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.

Cardiac thrombus associated with Mycoplasma pneumoniae infection.

Thrombosis is a very rare complication of Mycoplasma pneumoniae infection. We report the case of a previously healthy nine-year-old boy with cardiac thrombus in the right ventricle associated with M. pneumoniae pneumonia. This cardiac thrombus was detected eight days after the onset of respiratory symptoms. The mechanism underlying thrombosis may be related to autoimmune modulations and was attributable to the production of transient antiphospholipid antibodies.

Anomalous subaortic left brachiocephalic vein in surgical cases and literature review.

Anomalous subaortic left brachiocephalic vein (ASLBV) is a rare systemic venous anomaly. We review our experience with patients associated with ASLBV who underwent cardiac surgery at three institutions. From 1989 to 2009, the medical records of surgically treated patients with ASLBV were analyzed; the incidence of ASLBV, clinical characteristics, and associated anatomical findings were assessed. Fifteen patients had ASLBV. All ASLBVs coursed left lateral to the aortic arch, passed under the ascending aorta anterior to the central pulmonary artery, and joined the right brachiocephalic vein. Fourteen patients had congenital heart disease (CHD), and the remaining patient did not have cardiac anomalies. Its incidence was 0.57% (14 of 2,449) in patients with CHD and only 0.02% (1 of 4,805) in patients without CHD. In patients with CHD, 73.3% (11 of 15) of the patients had conotruncal cardiac anomalies such as tetralogy of Fallot, ventricular septal defect with pulmonary atresia, truncus arteriosus, and interruption of the aortic arch. Eight patients had aortic arch anomalies, including right aortic arch and cervical aortic arch. The deletion of chromosomal 22q11.2 was confirmed in two patients, and one patient was diagnosed with DiGeorge syndrome. ASLBV was clinically silent even without any surgical intervention. ASLBV is a very rare anomaly and is highly associated with conotruncal cardiac anomalies and aortic arch anomalies, including right aortic arch and cervical aortic arch. Preoperative diagnosis is important when any surgical interventions are intended, especially, in patients with conotruncal cardiac anomalies. Clin. Anat. 23:950–955, 2010.

Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life.

BACKGROUND We investigated the effects of fetal growth restriction (FGR) induced by maternal protein restriction on inflammatory vascular remodeling using a cuff-induced vascular injury mouse model. METHODS Dams (C57BL/6J strain mice) were fed an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of age until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When offspring were 10 weeks of age, vascular injury was induced by polyethylene cuff placement around the femoral artery. RESULTS Birth weight in offspring from dams fed LP until delivery (LPO) was significantly lower, but body weight was the same at 2 weeks after birth compared with that in NP offspring (NPO). Arterial blood pressure at 12 weeks of age did not differ between LPO and NPO. Neointima formation was exaggerated in LPO compared with NPO and associated with an increase in cell proliferation assessed by proliferating cell nuclear antigen (PCNA) staining index. Moreover, LPO showed enhanced expression of monocyte chemotactic protein-1, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and production of superoxide anion in the injured artery. Moreover, mRNA expression of isoforms of NAD(P)H oxidase subunits such as p22phox, p40phox, p47phox, p67phox, gp91phpx, and Rac1 in the injured arteries were enhanced in LPO. Furthermore, HIF-1α expression was increased in LPO compared with that in NPO. CONCLUSIONS These results suggest that maternal low-protein diet-induced FGR increases susceptibility of the vasculature to postnatal injury.

Life-threatening acute renal failure due to imperforate hymen in an infant.

Imperforate hymen (IH) is the most frequent congenital malformation of the female genital tract. The estimated incidence of IH is 0.014–0.1%. Girls with IH are typically asymptomatic until adolescence, when uterovaginal secretions and menstrual blood distend the vagina and uterus, resulting in intermittent pelvic pain. In rare cases maternal estrogen may stimulate uterovaginal secretions and cause hydrometrocolpos in newborns and young infants with IH. Acute renal failure in infants may be caused by various factors, including genital tract atresia, but it is difficult to diagnose genital atresia as a cause of acute renal failure. We treated a 35-day-old infant girl with IH accompanied by severe venous dilatation in the inguinal region. This patient suffered from acute renal failure caused by renal tract obstruction. We herein present a case report and a review of the relevant literature.

Procalcitonin as a marker of respiratory disorder in neonates

Serum procalcitonin (PCT) increases in various respiratory disorders such as acute respiratory distress syndrome. Elevated PCT is also observed in healthy neonates. In this study, we investigated whether PCT is a good marker of respiratory disorder in neonates.

Successful Revascularization by Pulse Infusion Thrombolysis in a Patient With Kawasaki Disease Combined With Acute Myocardial Infarction

A 24-year-old man was admitted to our hospital because of continuous anterior chest discomfort. He had a history of Kawasaki disease. He was diagnosed with an ST-segment elevation myocardial infarction, showing thrombotic occlusion of an aneurysm in the right coronary artery ([Fig. 1][1]A). Thrombus

Asynchronous contraction of the 2 ventricles caused by ventricular pacing after a Fontan-type operation in a patient with a biventricular heart

We treated a 6-year-old boy who had polysplenia syndrome and tetralogy of Fallot with a small right ventricle (RV), an atrial septal defect, a hemiazygos connection, and bilateral superior vena cava. Because the RV was too small for a biventricular repair to be performed, the patient underwent a total cavopulmonary shunt operation although his heart was biventricular and a pacemaker (VVI) had been implanted for management of the sick sinus syndrome complicated by polysplenia syndrome. After the operation, marked asynchronous contraction was noted between the morphological right and left ventricles and was probably responsible for the low cardiac output noted in this patient. In order to clarify the significance of the asynchronous contraction, we determined the cause of the low cardiac output by studying the time course of the volume changes in the morphological right and left ventricles during a cardiac cycle by using angiograms. In addition, we studied the interventricular flow dynamics by using pulsed-Doppler echocardiography. After a Fontan-type operation is performed on patients with a biventricular heart, the 2 ventricles may not function in perfect coordination when they have to work as 1 unit. These patients are likely to develop cardiac dysfunction due to interventricular to-and-fro flow dynamics. Asynchronous contraction between the 2 ventricles caused by abnormal interventricular conduction impaired the cardiac performance in the present case.