Gene polymorphism of myospryn (cardiomyopathy-associated 5) is associated with left ventricular wall thickness in patients with hypertension.

We examined a gene polymorphism of a novel Z-disc-related protein, myospryn (cardiomyopathy-associated 5). We focused on one haplotype block associated with a tag single nucleotide polymorphism (SNP) that covered 16 of 27 coding SNPs with linkage disequilibrium (minor allele frequency 0.413). Screening a myospryn polymorphism (K2906N) in a general health check-up of a rural Japanese population revealed an association with cardiac diseases (p=0.0082). In further analysis of the interaction between K2906N and cardiac function in patients, K2906N was associated with the anteroseptal wall thickness of the left ventricle in a recessive model (p=0.0324) and with the ratio of the peak velocity of the early diastolic filling wave to the peak velocity of atrial filling (A/E) (p=0.0278). In an association study based on left ventricular wall thickness, we found a significant difference in the K2906N genotype between controls and patients with cardiac hypertrophy. These results suggest that the K2906N polymorphism could be clinically associated with left ventricular hypertrophy and diastolic dysfunction independent of known parameters. Although the precise mechanism underlying this association remains to be elucidated, treatment with angiotensin II induced an increase in heart myospryn mRNA level in vitro and in vivo. Our results suggest that the polymorphism of myospryn is associated with left ventricular hypertrophy, and an association between a Z-disc protein and cardiac adaptation in response to pressure overload.     

The effects of chymase on matrix metalloproteinase-2 activation in neointimal hyperplasia after balloon injury in dogs.

Chymase is known to generate angiotensin II in the vascular wall. In this study we investigated a novel role for chymase other than angiotensin II production in vascular proliferation after balloon injury. Chymase promoted the migration of vascular smooth muscle cells in the matrix-coated invasion chambers and activated promatrix metalloproteinase-2 obtained from the culture medium of vascular smooth muscle cells. Two weeks after balloon injury, significant neointimal formation was found in dog carotid arteries. After injury, active matrix metalloproteinase-2 was increased in parallel with the augmentation of chymase activity that was seen in the proliferating region of the vascular wall. The oral administration of NK3201 (1 mg/kg per day), a chymase inhibitor, prevented neointimal formation and significantly suppressed both active matrix metalloproteinase-2 and chymase activities 2 weeks after injury. These results suggest that chymase inhibitors can prevent the development of intimal hyperplasia via the inhibition of matrix metalloproteinase-2 activation in balloon-injured arteries.     

Effect of nasal continuous positive airway pressure treatment on plasma adrenomedullin levels in patients with obstructive sleep apnea syndrome: roles of nocturnal hypoxia and oxidant stress.

Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress and oxidative stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients as compared to an age and body mass index (BMI)-matched control group and an age-matched, but normal-BMI control group. We further hypothesized that nasal continuous positive airway pressure (nCPAP) treatment may decrease OSAS-induced hypoxic stress, oxidative stress and ADM levels. To examine these hypotheses, we measured circulating ADM and reactive oxygen species (ROS) from leukocytes before and after nCPAP therapy in OSAS patients. The circulating levels of ADM and amount of ROS in untreated OSAS patients were significantly greater than those in the controls. No differences in ADM levels were found between the increased-BMI controls and normal-BMI controls. We observed that nCPAP treatment decreased sleep apneas, nocturnal oxyhemoglobin desaturation, the circulating ADM, and ROS production by leukocytes in OSAS patients. The ADM levels were associated with the magnitude of oxyhemoglobin desaturation rather than the number of sleep apneas. These observations suggest that nCPAP therapy could reduce OSAS-induced nocturnal hypoxemia, generation of ROS, and ADM in patients with OSAS.     

Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II.

Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.     

Effect of S-8666 on Cl- transport in the rabbit connecting tubule perfused in vitro.

S-8666, [6, 7-dichloro-5-(N, N-dimethylsulfamoyl)-2, 3-dihydrobenzofurancarboxylic acid] is a potent diuretic with uricosuric action. Although the major site of action of S-8666 has been proven by the in vitro microperfusion study to be the thick ascending limb of Henle's loop, clearance studies in the rat suggested that this drug has an additional thiazide-like action. To provide direct evidence that S-8666 acts also on distal nephron segments, we examined effect of S-8666 on Cl- flux across the rabbit connecting tubule perfused in vitro. The drug suppressed the lumen-to-bath Cl- flux by 96 +/- 41 (S.E.)pmol.mm-1.min-1 (n = 9) without affecting transmural voltage. To demonstrate that S-8666 acts on the connecting tubule cell, the target of thiazide diuretics, we compared effects of S-8666 and trichlormethiazide on the basolateral membrane voltage of the connecting tubule cell. Both drugs added to the lumen caused a small but significant hyperpolarization of the basolateral membrane without affecting transmural voltage. We conclude that S-8666 is a unique uricosuric diuretic having actions on both thick ascending limb of Henle's loop and connecting tubule.     

Pathological and biochemical studies on a case of Pick disease with severe white matter atrophy

We report on a male patient with Pick disease who had shown severe white matter atrophy and dilatation of the lateral ventricle in the frontal lobe from an early stage. Upon admission to our hospital 2 years after disease onset, the patient showed apathy, and MRI revealed severe atrophy of the cortex and white matter of the frontal lobe. He died at age 74, 11 years after disease onset. Autopsy revealed severe atrophy of the frontal and temporal lobes, severe loss of white matter in the frontal lobe, dilatation of the lateral ventricles, and cortical thinning. Histopathological examination showed severe loss of myelinated fibers in the frontal white matter and severe neuronal loss with gliosis in the frontal and temporal cortices. Many Pick bodies were seen. Our patient had a rare case of Pick disease predominantly affecting the frontal lobe with severe involvement of the white matter from an early stage. This case suggests that myelinated fibers in the white matter as well as cerebral neurons are primarily affected in Pick disease.     

Extremely Well Differentiated Papillary Adenocarcinoma of the Lung with Prominent Cilia Formation

We describe a 54-year-old woman with primary pulmonary adenocarcinoma showing a characteristic papillary architecture and prominent cilia formation. Immunohistochemically, the tumor cells were positive for carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) and Leu Ml, and negative for lactoferrin and surfactant apoprotein. An ultrastructural study also indicated differentiation toward bronchial surface epithelial cells. To our knowledge, this type of neoplasm has not been reported as peripheral-type adenocarcinoma of the lung. Acta Pathol Jpn 42: 745–750, 1992.