Chikako Nakama

Differences between daytime and nighttime blood pressure variability regarding systemic atherosclerotic change and renal function

Recently, new parameters related to hypertension, such as variability in blood pressure and ambulatory arterial stiffness index (AASI), were demonstrated to correlate with arteriosclerotic change. In this study, we investigated the correlation between circadian variability in blood pressure/AASI and renal function. We also investigated differences in the clinical impact of 24 h, daytime and nighttime blood pressure variability on renal and systemic atherosclerotic changes. We analyzed data from 120 patients who underwent renal Doppler ultrasonography (RDU) and ambulatory blood pressure monitoring (ABPM) at our hospital ward, and investigated the correlation between circadian variability in blood pressure/AASI and renal function, including resistive index (RI) evaluated with RDU, which is thought to be a good indicator of renal vascular resistance. Subjects with higher circadian variability in systolic blood pressure (SBP) had significantly higher RI. Daytime variability in SBP correlated more strongly with RI than nighttime variability. Meanwhile, only nighttime variability, but not daytime variability, in SBP was related to carotid atherosclerosis. Similarly, AASI was significantly correlated with RI. Circadian variability in SBP and AASI were both significantly correlated with renal function. Daytime SBP s.d. was especially more strongly correlated with renal vascular resistance, and nighttime SBP s.d. was significantly correlated with intima-media thickness (IMT) and plaque score. These results indicate that evaluating both daytime and nighttime blood pressure variability enables an assessment of pathological conditions in hypertensive patients to prevent cardiovascular diseases.

Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor

The angiotensin II type 1 receptor (AT1) is a 7‐transmembrane domain GPCR that when activated by its ligand angiotensin II, generates signaling events promoting vascular dysfunction and the development of cardiovascular disease. Here, we show that the single‐transmembrane oxidized LDL (oxLDL) receptor (LOX‐1) resides in proximity to AT1 on cell‐surface membranes and that binding of oxLDL to LOX‐1 can allosterically activate AT1‐dependent signaling events. oxLDL‐induced signaling events in human vascular endothelial cells were abolished by knockdown of AT1 and inhibited by AT1 blockade (ARB). oxLDL increased cytosolic G protein by 350% in Chinese hamster ovary (CHO) cells with genetically induced expression of AT1 and LOX‐1, whereas little increase was observed in CHO cells expressing only LOX‐1. Immunoprecipitation and in situ proximity ligation assay (PLA) assays in CHO cells revealed the presence of cell‐surface complexes involving LOX‐1 and AT1. Chimeric analysis showed that oxLDLinduced AT1 signaling events are mediated via interactions between the intracellular domain of LOX‐1 and AT1 that activate AT1. oxLDL induced impairment of endothelium‐dependent vascular relaxation of vascular ring from mouse thoracic aorta was abolished by ARB or genetic deletion of AT1. These findings reveal a novel pathway for AT1 activation and suggest a new mechanism whereby oxLDL may be promoting risk for cardiovascular disease.—Yamamoto, K., Kakino, A., Takeshita, H., Hayashi, N., Li, L., Nakano, A., Hanasaki‐Yamamoto, H., Fujita, Y., Imaizumi, Y., Toyama‐Yokoyama, S., Nakama, C., Kawai, T., Takeda, M., Hongyo, K., Oguro, R., Maekawa, Y., Itoh, N., Takami, Y., Onishi, M., Takeya, Y., Sugimoto, K., Kamide, K., Nakagami, H., Ohishi, M., Kurtz, T. W., Sawamura, T., Rakugi, H. Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin‐like oxLDL receptor. FASEB J. 29, 3342‐3356 (2015). www.fasebj.org

The influence of aging on the diagnosis of primary aldosteronism

Primary aldosteronism (PA) is common in young or middle-aged hypertensive patients, but PA among the elderly has recently become more common. As salt sensitivity increases with age, plasma renin activity (PRA) tends to decrease, whereas the aldosterone-to-renin ratio (ARR) tends to increase in the elderly. The aim of this study was to clarify the influence of aging on the diagnosis of PA. We retrospectively evaluated 155 consecutively admitted patients who were not taking antihypertensive medications or calcium channel blockers and α blockers that underwent PRA and plasma aldosterone concentration (PAC) measurements. The study subjects included 13 PA and 69 essential hypertensive (EHT) patients aged over 65 years, and 32 PA and 41 EHT patients under aged 65 years. Our study clarified the influence of aging through screening and confirmatory tests for the diagnosis of PA. Our results showed the ARR cutoff value for a screening test to be 556 (area under the curve: AUC=0.906), its sensitivity and specificity to be 84.6% and 89.9%, respectively, and the likelihood ratio to be 8.34 in the elderly, whereas the ARR cutoff value was 272 in the non-elderly. In the saline infusion test, the mean PAC was 86.6±41.8 pg ml−1 in the elderly and 158.1±116.5 pg ml−1 in the non-elderly (P=0.04). There was no influence from age in both the captopril challenge test and the furosemide upright test. Aging may influence PA screening and saline infusion tests; thus, we should consider the influence of aging in the diagnosis of elderly subjects with PA.

Differences in the association between high blood pressure and cognitive functioning among the general Japanese population aged 70 and 80 years: The SONIC study

High blood pressure in middle age (up to 64 years) has been proposed as a predictive indicator of dementia. However, the association between hypertension and the cognitive functioning is controversial in older age groups. The aim of this study was to investigate this association in 70–80-year-old participants in the Japanese study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC). Participants aged 70 (±1) and 80 (±1) years (n=1000 and 973, respectively) were randomly recruited from the general population in Japan. Cognitive functioning was measured by the Montreal Cognitive Assessment. Blood pressure and other medical and social variables were analyzed by multiple regression analyses. High systolic blood pressure (SBP) was significantly correlated with a reduced cognitive functioning only in participants aged 70 years. Additionally, this correlation became more marked in participants with uncontrolled blood pressure at age 70 years. In contrast, SBP was not significantly correlated with the cognitive functioning at age 80 years. Nutritional status indicators such as serum albumin and frequency of going outdoors were significantly associated with cognitive functioning at age 80 years. Our findings indicate that high SBP has a significant role in cognitive functioning at age 70 years; however, blood pressure is less important as a risk factor for cognitive decline at age 80 years.

Association Analysis of FOXO3 Longevity Variants with Blood Pressure and Essential Hypertension

BACKGROUND The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)- rs2802292 , rs2253310 , and rs2802288 -are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry. RESULTS In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. CONCLUSION Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.

Disease-associated polymorphisms in 9p21 are not associated with extreme longevity.

The 9p21 region has been pointed out by the genome‐wide association studies as a hot spot for disease‐associated variants. Most of the diseases linked with the locus are aging‐related conditions, such us cardiovascular disease, diabetes and cancer. Centenarians are known to present a reduced risk and delayed onset for these conditions. Here, we aimed to assess if the 9p21 variants contribute to this protection by possibly altering basic aging mechanisms.

Longitudinal association of hypertension and diabetes mellitus with cognitive functioning in a general 70-year-old population: the SONIC study

Both hypertension and diabetes in middle-aged individuals have been suggested to be predictive indicators of cognitive decline. However, the association of hypertension, diabetes and their combination with cognitive functioning is still controversial in older people. The purpose of this study was to investigate the association between cognitive decline and hypertension, diabetes, and their combination in 70-year-old people based on a 3-year longitudinal analysis. Four hundred and fifty-four people aged 70 (±1) years who participated in the Japanese longitudinal cohort study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC) were recruited randomly from a general population and were monitored for 3 years. The data, including most of the demographics, cognitive functioning measured by the Montreal Cognitive Assessment Japanese version (MoCA-J), blood pressure, blood chemistry and other medical histories, were collected at baseline and during the follow-up. The prevalence of hypertension noted in the follow-up survey was significantly higher than than noted at baseline. The mean MoCA-J score at follow-up was not significantly different from the score obtained at baseline. However, the participants with diabetes, especially combined with hypertension at baseline, had significantly lower MoCA-J scores than those without lifestyle-related diseases. The combination of hypertension and diabetes was still a significant risk factor for cognitive decline, considering the MoCA-J scores obtained during the follow-up after adjustments at baseline, relative to sex, body mass index, dyslipidemia, smoking, excessive alcohol intake, antihypertensive treatment and education level (β=−0.14; P<0.01). Our findings indicate that diabetes and the combination of hypertension and diabetes are clear risk factors for future cognitive decline in elderly individuals who are 70 years of age.

Relationship between atherosclerosis and occlusal support of natural teeth with mediating effect of atheroprotective nutrients: From the SONIC study

Whereas most of studies investigating relationship between oral health and atherosclerosis have focused on periodontitis, very few of them were examined about occlusal status of natural teeth which possibly influence dietary habit. The primary aim of this cross-sectional study was to investigate the association between the occlusal support of posterior teeth and the prevalence of atherosclerosis in community-dwelling septuagenarians. Also, the second aim was to test the hypothesis that the intake of key nutrients for atherosclerosis prevention would have a mediating effect on the relationship between the occlusal status and atherosclerosis. The study population included 468 community-dwelling dentate persons aged 69–71 years recruited from the local residential registration in Japan. Participants were divided into three groups, according to the number of occlusal support zones (OSZ) in the posterior area: Complete (four OSZ), Moderate (three or two OSZ), and Collapsed (one or no OSZ). Dietary intakes were assessed using a brief-type self-administered diet history questionnaire. Atherosclerosis was defined as carotid intima-media thickness ≧1.10 mm by using carotid ultrasonography test. The logistic or linear regression model was used in multivariate analysis to assess relationship between occlusal status and atherosclerosis, and the mediating effect of key nutrients within the relationship. Multivariable analysis showed a significant association between occlusal status and atherosclerosis (odds ratio for Collapsed group to Complete group: 1.87; 95% CI: 1.45–2.41), independent of periodontal status (odds ratio: 2.01, 95%CI: 1.46–2.78). Fish and shellfish, vitamin B6 and n-3PUFAs were significantly related to both of occlusal status and atherosclerosis, and also was indicated a mediating effect on the association between occlusal status and atherosclerosis. This study implied that, within the limitation of the cross-sectional study design, the reduced posterior occlusion was related to the increased prevalence of atherosclerosis via the decline of key dietary intakes among Japanese community-dwelling dentate individuals.

831 CAROTID INTIMA MEDIA THICKNESS IS MORE STRONGLY ASSOCIATED WITH PULSE PRESSURE THAN SYSTOLIC BLOOD PRESSURE IN 70 YEARS ELDERLY

Background: Pulse pressure (PP) is supposed to be a good maker of vascular stiffness. Although PP was reported to be associated with cardiovascular events in the elderly, physicians didn’t pay much attention to PP compared to blood pressure (BP). Past studies suggested that PP was associated with carotid intima-media thickness (IMT), however aging that was the strongest confounding factor for IMT might be influencing on the results of previous studies. The purpose of this study is to reveal the association of carotid IMT with BP or PP without the influence of age. Methods: We analyzed 489 elderly (70 ± 1 y.o.) in Japanese general population. We performed carotid ultrasound and general physical examination, and assessed the association of common carotid mean IMT with BP or PP. Results: In univariate analysis, carotid IMT was significantly associated with systolic BP (SBP) and PP (P < 0.05). In multivariate analysis adjusted by confounding factors, IMT was significantly associated with PP (P < 0.05) and not with SBP. The cutoff PP value for carotid atherosclerosis (IMT≥1.1 mm) from ROC curve was 62 mmHg, and the IMT value in the subjects with PP ≥ 62mmHg was thicker than with SBP ≥ 140 mmHg. Conclusions: In 70 years elderly, PP was more strongly associated with carotid IMT than SBP. This result suggests that clinician would effectively detect the elderly with carotid atherosclerosis to pay attention to PP. In order to prevent cardiovascular events, the subject with PP≥ 62mmHg should be considered to exam the atherosclerosis such as the carotid ultrasound.

641 EFFECT OF AGING ON VARIOUS CONFIRMATORY TESTS AND ADRENAL VEIN SAMPLING FOR PRIMARY ALDOSTERONISM DIAGNOSIS

Background: It is known that primary aldosteronism (PA) accounts for 5–10% in patients with hypertension. Since the salt sensitivity is getting stronger according to aging, plasma renin activity (PRA) and aldosterone concentration (PAC) tends to be low level. The aim of this study is to clarify influence of aging on various confirmatory tests and adrenal vein sampling (AVS) for PA diagnosis. Methods: Study subjects are admitted 40 PA patients. We divide into 25 patients under 60 years old (44.0 ± 9.3 y.o.) and 15 patients over 60 years old (68.0 ± 5.6 y.o.) and we examined influence of aging on various confirmatory tests for PA diagnosis. Furthermore, we examined influence of AVS for 11 patients under 60 years old and 6 patients over 60 years old who received ACTH loaded AVS and diagnosed as aldosterone producing adenoma (APA). Results: The mean PRA (ng/ml/hr) and PAC (pg/ml) are not significantly different between old and non-old groups. In saline loading tests, the mean PAC are 163.2 ± 21.0 in the non-elderly and 87.8 ± 26.4 in the elderly (p = 0.03). In captopril suppression tests, there are no significant differences. In AVS, PAC after ACTH stimulation in non-tumor side are 4824 ± 3179 in the non-elderly and 11175 ± 9687 in the elderly (p = 0.11) and laterality ratio are also not significantly different between two groups (32.5 ± 25.8 in the non-elderly vs.13.3 ± 12.7 in the elderly). Conclusions: The saline loading test but not the captopril suppression test or AVS may be significantly influenced by aging because of low PAC level in the elderly.