Yasuyuki Tsujita

Genetic Polymorphism of CYP11B2 Gene and Hypertension in Japanese

Low-renin hypertension is characterized by a high ratio of aldosterone to plasma renin activity (ALD/PRA), which may suggest inappropriately increased aldosterone biosynthesis. The genes for the enzymes involved in aldosterone synthesis may contribute to low-renin hypertension. We investigated the associations between genetic variations of CYP11B2 (aldosterone synthase) T(-344)C and hypertension in 482 Japanese subjects. Subjects older than 50 years with a blood pressure <140/85 mm Hg were considered normotensive (n=227 subjects), and subjects younger than 65 years old with a BP >160/95 mm Hg were considered hypertensive (n=255 subjects). The frequency of the TC+CC genotypes in the normotensive group was significantly lower than in the hypertensive group. Logistic analysis on 482 subjects revealed that body mass index, gender, and the genotype of CYP11B2 T(-344)C were significantly associated with hypertension. ALD and PRA were assessed in 97 subjects with hypertension, and the TC+CC genotypes were significantly associated with higher ALD/PRA. Sixty-five subjects with hypertension were assessed by 24-hour ambulatory blood pressure monitoring, and the frequency of nondippers (a difference in mean blood pressure of <10% between the daytime [6 AM to 9 PM] and nighttime [9 PM to 6 AM] hours) was significantly higher in subjects with the TC+CC (hetero+homo mutation) genotype than in subjects with the TT (wild-type) genotype. Echocardiographic assessment (n=136) revealed that the ratio of left ventricular end-diastolic dimension to height tended to be higher in subjects with the TC+CC genotype than in subjects with the TT genotype. The present study suggests that the (-344)C allele of the CYP11B2 gene may be a genetic marker for low-renin hypertension in Japanese.

Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy

The serine/threonine kinase Akt regulates cellular survival, proliferation, gene transcription, protein translation, metabolism, and differentiation. Although Akt substrates are found throughout the cell, activated Akt normally accumulates in the nucleus, suggesting that biologically relevant targets are located there. Consequences of nuclear Akt signaling in cardiomyocytes were explored by using nuclear-targeted Akt (Akt-nuc). Accumulation of Akt-nuc did not provoke hypertrophy, unlike constitutively activated Akt. Instead, Akt-nuc inhibited hypertrophy concurrent with increased atrial natriuretic peptide (ANP) expression that depended upon phosphatidylinositol-3 kinase activity. Akt-nuc antihypertrophic effects were blocked by inhibition of either guanylyl cyclase A receptor or cyclic guanosine monophosphate-dependent protein kinase in cultured cardiomyocytes. Corroborating evidence showed blunted acute hypertrophic remodeling in Akt-nuc transgenic mice after transverse aortic constriction coincident with higher ANP expression and smaller myocyte volume. In addition, Akt-nuc expression improved systolic function and survival in the chronic phase of transverse aortic constriction-induced hypertrophy. Thus, Akt-nuc antagonizes certain aspects of hypertrophy through autocrine/paracrine stimulation of a phosphatidylinositol-3 kinase-dependent signaling cascade that promotes ANP expression, resulting in a unique combination of prosurvival coupled with antihypertrophic signaling.

Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study.

Objectives Endothelium-derived nitric oxide plays a key role in the regulation of vascular tone. Recently, endothelial nitric oxide synthase (eNOS) gene polymorphisms were reported to be associated with hypertension or coronary spasm. We investigated the association between the eNOS gene polymorphisms and hypertension in a large population-based sample of 4055 Japanese. Design and methods We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(−786)C polymorphism of the promoter region. The genotype distribution in hypertensive subjects was compared to that in the other subjects. The influence of the genotype on blood pressure values was analyzed in the subjects not taking hypertensive medication. The promoter activities of the eNOS gene with the (−786)T or (−786)C allele were measured by a luciferase reporter gene assay. Results There was significant linkage disequilibrium between the two polymorphisms (P < 0.0001). The genotype distribution of the Glu298Asp or T(−786)C polymorphism did not differ between the hypertensive and the other subjects. No significant differences in the blood pressure of subjects not taking hypertensive medication were observed among the three genotypes of Glu298Asp or T(−786)C polymorphisms. No significant differences in the promoter activity were observed between bovine endothelial cells transfected with the (−786)T and (−786)C alleles. Conclusions Our data suggested that these polymorphisms of the eNOS gene are unlikely to be major factors in the susceptibility to hypertension in the Japanese population studied.

Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels

UNLABELLED Moderate drinkers with a defective alcohol dehydrogenase type 3 (ADH3) genotype have higher high-density lipoprotein (HDL) levels and a decreased risk of coronary artery disease (CAD). We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan. The ALDH2 genotype of each subject was determined by polymerase chain reaction (PCR) analysis. HDL was adjusted for the alcohol intake, age, body mass index, smoking status, total cholesterol, triglycerides and HbA1c levels. None of the subjects had a history or ECG suggestive of CAD. The proportions of ALDH2, *1/*1, *1/*2, and *2/*2 (defective homozygote) were 45.8, 46.0, and 8.2%, respectively, for men. Drinking more than two drinks daily was associated with lower HDL levels in men with the defective genotypes compared with men with a normal genotype (55.6+/-0.9 vs. 51.2+/-0.9 mg/dl, mean+/-S.E., P<0.0001). Also, drinking more than 0.5 drinks daily was not associated with beneficial effects on HDL levels in women with defective ALDH2 genotypes. CONCLUSIONS Alcohol intake did not have beneficial effects on HDL levels in the defective ALDH2 genotype and may not protect against CAD in subjects with defective ALDH2 genotypes.

Isolation of a Chromosome 1 Region That Contributes to High Blood Pressure and Salt Sensitivity

Linkage analyses in the spontaneously hypertensive rat (SHR) suggest that a gene involved in blood pressure regulation may be located on rat chromosome 1, in the Sa region. To confirm this possibility, we replaced a region of chromosome 1 in the Wistar-Kyoto rat (WKY) defined by the markers D1Mit3 and MTPA with the corresponding chromosome segment from SHR. Genotyping using 65 polymorphic microsatellite markers throughout the entire genome confirmed the congenic status of this new strain designated WKY. SHR-D1Mit3/Rat57. In male WKY.SHR-D1Mit3/Rat57, mean blood pressures in the daytime and in the nighttime assessed by radiotelemetry were significantly higher than those in male progenitor WKY. Moreover, salt loading significantly increased the mean blood pressure in male WKY.SHR-D1Mit3/Rat57 but not in male progenitor WKY. The present study confirmed the existence of a gene that contributes to high blood pressure and salt sensitivity in this chromosomal segment. This congenic strain represents a new animal model for fine mapping and characterization of the gene in this region involved in salt-sensitive hypertension.

Relationship between metabolic syndrome and Trp64Arg polymorphism of the β3-adrenergic receptor gene in a general sample: The Shigaraki study

It has been reported that the β3-adrenergic receptor gene (ADRB3) is associated with abnormal metabolic risk factors. Therefore, we examined whether the Trp64Arg polymorphism of ADRB3 affects the occurrence of metabolic syndrome (MS). The participants were 2,395 subjects who underwent a medical examination in Shigaraki in Shiga, Japan. Among them, 1,416 subjects who gave informed consent for genetic analysis and were not receiving treatment for hypertension, diabetes, or hyperlipidemia were enrolled in this study. MS was diagnosed in 86 (16.0%) of 537 men, and 8 (0.9%) of 879 women. There was no significant relationship between ADRB3 polymorphism and the frequency of MS. Multiple logistic regression analysis including smoking, sex, and age as confounding factors showed no interaction between MS and ADRB3 polymorphism (odds ratio: 0.94; 95% confidence interval: 0.59–1.49; p=0.78). Subjects were also analyzed according to differences in the number of abnormal metabolic risk factors. However, there was no significant relationship between ADRB3 polymorphism and the number of such factors. In conclusion, in a general sample, the frequency of MS was 16.0% in men, and 0.9% in women. There was no relationship between ADRB3 polymorphism and MS.

Combined Analysis of Polymorphisms in Angiotensinogen and Adducin Genes and Their Effects on Hypertension in a Japanese Sample: The Shigaraki Study

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Thr or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06–1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13–1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16–1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18–2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03–1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.

Variant of the β3-adrenergic receptor gene and coronary atherosclerosis in Japanese subjects

In the present study, we assessed the significance of the Trp64Arg mutation in the beta3-adrenergic receptor gene in 428 Japanese subjects, including 198 subjects who underwent coronary angiography for possible ischemic heart diseases (IHD group) and 230 non-IHD subjects (control group). We conclude that the Trp64Arg polymorphism of the beta3-adrenergic receptor gene did not appear to have any pathophysiological significance in Japanese subjects.

Association of the Plasma Platelet-Derived Microparticles to Platelet Count Ratio with Hospital Mortality and Disseminated Intravascular Coagulopathy in Critically Ill Patients

AIM The role of platelet-derived microparticles (PDMPs) in the crosstalk between coagulopathy and inflammation in critically ill patients remains unclear. The aim of this cohort observational study was to investigate the associations between the PDMP levels and hospital mortality or disseminated intravascular coagulopathy (DIC). METHODS This study included 119 patients who were admitted to the ICU. The PDMP levels were measured using an enzyme-linked immunosorbent assay three times a week, for a total of 372 samples. We calculated the maximum (max) PDMP value, max PDMP/platelet (PDMP/Plts) ratio (converted to the PDMP levels per 10(4) platelets) and nadir platelet count during the ICU stay. Baseline patient data and scores, including the Japanese Association for Acute Medicine (JAAM) DIC score, were collected, and potential predictors were analyzed for possible associations with hospital mortality. RESULTS The max PDMP/Plts ratio was significantly different comparing the survivors (n=98: median, 2.54) and non-survivors (n=21: median 17.59; p＜0.001). There was a weak but statistically significant negative correlation between the max PDMP level and nadir platelet count (r=-0.332, p＜0.001). The max PDMP level and max PDMP/Plts ratio were higher in the DIC group (81.48 and 9.27, respectively) than in the non-DIC group (34.88 and 2.35, p=0.001 and p＜0.001, respectively). The max PDMP/Plts ratio was the only variable found to be independently associated with hospital mortality according to a multivariate logistic regression analysis. CONCLUSIONS PDMPs are involved in the development of DIC but are not related to hospital mortality. There is a good association between the PDMP/Plts ratio and hospital mortality and/or DIC in critically ill patients.

Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction

Landiolol effectively controls rapid heart rate in atrial fibrillation or flutter (AF/AFL) patients with left ventricular (LV) dysfunction. However, predicting landiolol Responders and Non‐Responders and patients who will experience adverse effects remains a challenge. The aim of this study was to clarify the potential applicability of landiolol for rapid AF/AFL and refractory ventricular tachyarrhythmias (VTs) in patients with heart failure.