Yoshikuni Yamamoto

Association of Endothelin-1 Gene Variant With Hypertension

Abstract—Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells. Many lines of biological evidence suggest that the ET-1 gene is a candidate gene for hypertension. Moreover, recent association studies suggested that a G/T polymorphism with an amino acid substitution (Lys/Asn) at codon 198 in exon 5 of the ET-1 gene interacts with body mass index (BMI) in association with blood pressure. They suggested that T carriers are more sensitive to weight gain than GG homozygotes in association with blood pressure. However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. We therefore assessed the interaction in 2 large Japanese populations. The present study showed a nonsignificant but similar trend to the results of previous reports. Moreover, in line with previous reports, this study revealed a significant interaction between the ET-1 K198N (G/T) polymorphism and BMI in association with hypertension in our populations (P =0.027). The interaction was significant, even after adjustment for gender and age (P =0.045) and for all confounding factors (P =0.044). T carriers were more sensitive to weight gain than GG homozygotes in association with hypertension. Considering the combined impact of obesity and hypertension on the development of cardiovascular and cerebrovascular disorders, T allele carriers might represent elective targets for therapy to lower their body weight.

Association of GNAS1 Gene Variant With Hypertension Depending on Smoking Status

The &bgr;-adrenoceptor (&bgr;-AR) Gs protein system has been shown to have important roles in the cardiovascular system. The gene encoding the &agr;-subunit of Gs proteins (GNAS1) is a candidate genetic determinant for hypertension. We studied the GNAS1 T393C polymorphism in >2000 Japanese individuals. &khgr;2 test showed a marginally significant difference in the frequencies of the alleles (P =0.036) and genotypes (P =0.094) between hypertensives and normotensives. Because hypertension is considered to be a complex disorder resulting from interactions between genetic and environmental factors, we further analyzed the T393C polymorphism, with consideration of interactions between the polymorphism and confounding factors in regression models. These analyses showed a significant interaction between the polymorphism and cigarette smoking in the pathogenesis of hypertension (P =0.0005). The interaction was reflected in a significant association of the polymorphism with hypertension in nonheavy smokers (P =0.0028; odds ratio, 1.52; 95% confidence interval, 1.16 to 2.00). A significant interaction between the polymorphism and aging in the pathogenesis of hypertension was also shown in nonheavy smokers. These findings may be helpful in conducting further molecular and biological studies on the relationship among cigarette smoking, the &bgr;-AR-Gs protein system, and hypertension.

Association between carotid arterial remodeling and plasma concentration of circulating hepatocyte growth factor.

Background Several studies have reported that the circulating concentration of hepatocyte growth factor (HGF) was increased in individuals with clinically overt atherosclerotic disease, including coronary heart disease and peripheral arterial disease. However, whether changes in the circulating concentration of HGF are associated with early atherosclerotic changes in apparently healthy individuals remains to be determined. Objective To investigate the relationship between the plasma concentration of HGF and carotid arterial remodeling. Methods Plasma concentrations of HGF were measured in 201 community-dwelling healthy residents free from any medications and signs and history of cardiovascular disease. Carotid intima–media thickness (IMT) and carotid internal diameter were determined by ultrasonography with a 7.5 MHz probe. The study participants were divided into four groups according to the presence or absence of carotid atherosclerosis (presence of plaque, IMT ⩾ 0.85 mm) and carotid arterial dilatation (diameter ⩾ 7.0 mm). Results Carotid arterial remodeling, atherosclerosis or dilatation, or combinations thereof, was associated with significantly greater concentrations of plasma HGF. Among risk factors, plasma HGF was significantly associated with advanced age (⩾ 65 years), current smoking and diabetes mellitus, whereas sex, obesity, hypertension and hypercholesterolemia did not affect plasma concentrations of HGF. Multiple regression analysis showed that plasma HGF was independently associated with carotid arterial remodeling (atherosclerosis, dilatation, or both) in addition to age and systolic blood pressure. Conclusions These results indicate that the plasma concentration of HGF increases in relation to carotid arterial remodeling, independently of known risk factors for atherosclerosis. These findings further support a possible role of HGF in atherosclerosis.

Chlamydia pneumoniae Seropositivity Is Associated With Increased Plasma Levels of Soluble Cellular Adhesion Molecules in Community-Dwelling Subjects The Shimanami Health Promoting Program (J-SHIPP) Study

Background and Purpose— In vitro studies have demonstrated that Chlamydia pneumoniae infection of the endothelium increases the expression of adhesion molecules and chemokines, indicating that C pneumoniae infection affects the adhesion and recruitment of leukocytes to the endothelium, which is believed to be involved in the initial steps of atherosclerosis. However, whether chronic C pneumoniae infection increases these molecules in vivo has not been elucidated. Methods— The association between C pneumoniae seropositivity and plasma concentrations of soluble adhesion molecules and a chemokine was investigated in 200 community-dwelling residents free from cardiovascular diseases and medication. Plasma levels of IgA and IgG antibodies to C pneumoniae were measured by enzyme-linked immunosorbent assay. Indices of IgG and IgA antibodies were determined as the ratio to the standardized positive control. The subjects were divided into 3 groups according to the indices of antibodies:C pneumoniae seronegative (n=57, IgA<1.0 and IgG<1.0), C pneumoniae intermediate (n=81, 1.0≤IgA≥1.1 or 1.0≤IgG≥1.1), and C pneumoniae seropositive (n=62, IgA>1.1 and IgG>1.1). Plasma concentrations of soluble forms of intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1, and monocyte chemoattractant protein-1 were determined by enzyme-linked immunosorbent assay. Results— Plasma concentrations of ICAM-1 (392±118, 398±94, 470±154 ng/mL, P =0.0004) and vascular cellular adhesion molecule-1 (402±146, 419±130, 472±181 ng/mL, P =0.03) were significantly different among the C pneumoniae seronegative, intermediate, and seropositive groups respectively. However, plasma monocyte chemoattractant protein-1 was not significantly different among the 3 groups. Stepwise regression analysis showed that plasma concentration of ICAM-1 was significantly associated with C pneumoniae seropositivity, independent of other known risk factors for atherosclerosis and carotid intima-media thickness. Conclusion— These findings indicate that C pneumoniae seropositivity is associated with higher plasma concentrations of soluble forms of adhesion molecules in the general population. The increase in circulating adhesion molecules may underlie the mechanisms linking C pneumoniae infection and atherosclerosis in vivo.

Orthostatic hypertension: another orthostatic disorder to be aware of.

To the Editor: Orthostatic dysregulation of blood pressure is a disorder observed commonly in older people. 13 Orthostatic hypotension has become the focus of much research2•3 since epidemiological studies have revealed that orthostatic hypotension is associated with increased risk of death. 1 Less attention has been paid, however, to the finding of orthostatic hypertension in routine examinations. Recently, an association between orthostatic increase in blood pressure and higher predicted risk of developing coronary heart disease was reported in the ARIC study.4 In addition, orthostatic hypertension has been demonstrated to be related to cognitive impairment and asymptomatic cerebrovascular damage detected by MRI.5 These findings suggest that orthostatic dysregulation of blood pressure may be associated with atherosclerosis, although recent study has revealed that orthostatic hypotension was not associated with cognitive deterioration.2 We evaluated the prevalence of orthostatic dysregulation of blood pressure and its relationship with carotid atherosclerosis in 154 communitydwelling healthy subjects aged 65 years and older and free from any history or symptoms of cardiovascular disease and medications. After 10 minutes of rest in the supine position, brachial blood pressure was measured twice to obtain the mean basal blood pressure during ultrasound measurement of intima-media thickness (IMT) of the common carotid artery. Then blood pressure measurements were repeated at 1 and 3 minutes after standNOVEMBER 2000-VOL. 48, NO. 11 JAGS

Comprehensive studies of carotid atherosclerosis

Carotid atherosclerosis is closely associated with the progression of other atherosclerotic conditions, including ischemic heart disease and cerebral infarction. Evaluation of carotid atherosclerosis is useful as an index of systemic atherosclerosis, and is used as a surrogate endpoint in a number of clinical studies. We have been investigating several risk factors on the progression of atherosclerosis, using the carotid arteries as a window on the arterial system in general.

Supine hypertension with transient papilledema

A 68‐year‐old male, married, retired public official was admitted to hospital for thorough examination and appropriate treatment of gait disturbance and dizziness. He had been diagnosed with diabetes mellitus and hypertension for at least 28 years, and had been treated with insulin and antihypertensive medications intermittently at another hospital. We identified the major cause of his complaints as orthostatic hypotension, and controlled his casual systolic blood pressure (BP) to within the range of 140–160 mmHg in a sitting position. After a few weeks, on ophthalmic study, right papilledema was diagnosed. There was no progression of visual disturbance nor circulatory impairment in the optic fundi. Based on the results of 24‐h ambulatory BP monitoring, we assumed that his supine systolic hypertension triggered the papilledema, so we controlled his supine systolic BP to within the range of approximately 140–160 mmHg. After 2 weeks of controlled BP the papilledema improved. Visual disturbance was not reported during 1 year of follow up. In case of severe autonomic disorder such as orthostatic hypotension, attention should be paid to changes in the optic fundi, and ophthalmoscopic examination should be performed regularly.