[Sleep disturbance in elderly patients with dementia at home and the factors associated with its identification: An observational study].

AIMS: The purpose of this study was to objectively quantify the sleep of elderly patients with dementia at home using a device and to investigate the factors associated with its identification. METHODS: Sixteen patients (6 males [37.5%], 84.1±4.7 years old; and 10 patients with mild dementia [62.5%]) and their family caregivers who were using outpatient memory clinics and home-visiting nursing station in Japan were included. Demographic and clinical data of the patients and their family caregivers, subjective perceptions of patients' sleep, family caregivers' Zarit care burden, and whether or not they were aware of patients' sleep problems were determined. Nighttime sleep parameters were collected for one week using a non-wearable actigraph. Sleep parameters were compared with patients' subjective views and family caregivers' observations to investigate factors indicative of sleep disturbance. RESULTS: Nighttime sleep parameters for 1 week (mean) were follows: sleep efficiency, 77.2%±9.3%; asleep time, 442.3±99.9 minutes; sleep latency, 18.2±15.8 minutes; awake time, 105.1±69.7 minutes; and number of times leaving the bed, 4.6±3.8 (maximum of 29/night). A significant positive correlation was found between sleep efficiency and duration of dementia (r=0.53, p=0.046), while no correlation was found with dementia severity or Zarit care burden score. The agreement between the patients' complaints about sleep and sleep efficiency (75%) was 30.7%, and family caregivers' awareness of patients' nighttime awakening and bed-leaving was significantly associated with patients' incontinence (p=0.024) and a greater dementia severity (p=0.027). CONCLUSIONS: Elderly dementia patients experienced sleep disturbance at home, such as nighttime awakening and associated bed-leaving; however, it might be difficult to identify these patients at an early stage based on their own complaints and observations by family caregivers. Identifying sleep problems at an early stage may thus require the use of objective measurement devices.

Serum albumin/globulin ratio is associated with cognitive function in community-dwelling older people: The Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study.

AIM: The objective of this study was to clarify the relationship between cognitive function and the serum albumin/globulin ratio (A/G ratio) in community-dwelling Japanese older adults. METHODS: Randomly extracted residents in both urban and rural parts of Japan were enrolled in this study. A total of 1827 participants with a mean age of 70 or 80 years were recruited. A venue survey method was carried out with comprehensive studies, including interviews, blood collection, physical examination and cognitive function tests. RESULTS: Univariate analysis showed a significant positive correlation between the total Japanese version of the Montreal Cognitive Assessment score and the serum A/G ratio at the age of 70 and 80 years, in which better cognitive function was associated with a high serum A/G ratio. Multiple regression analysis with the total Japanese version of the Montreal Cognitive Assessment score as the dependent variable showed that the serum albumin level, serum globulin level, serum A/G ratio, C-reactive protein, years of formal education and sex were related to the Japanese version of the Montreal Cognitive Assessment total score at the age of 70 years, and that the serum albumin level, serum globulin level, serum A/G ratio, C-reactive protein, years of formal education and stroke were related at the age of 80 years. The serum A/G ratio showed a better correlation than the serum globulin levels at the age of 70 and 80 years (70 years: ß = 0.131 vs -0.111, 80 years: ß = 0.108 vs -0.071). CONCLUSIONS: We found a correlation between cognitive function and the serum A/G ratio in community-dwelling older people, suggesting that nutritional status and chronic inflammation might influence cognitive function. Geriatr Gerontol Int 2019; 19: 967-971.

Occlusal force is correlated with cognitive function directly as well as indirectly via food intake in community-dwelling older Japanese: From the SONIC study.

BACKGROUND: Growing evidence suggests that oral health may be an important factor associated with cognitive function in aged populations. However, many previous studies on this topic used insensitive oral indicators or did not include certain essential covariates. Thus, we examined the association between occlusal force and cognitive function in a large sample of older adults, controlling for dietary intake, vascular risk factors, inflammatory biomarkers, depression, and genetic factors. METHODS: In this cross-sectional study of older community-dwelling Japanese adults, we examined data collected from 994 persons aged 70 years and 968 persons aged 80 years. Cognitive function was measured using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral status and function were evaluated according to the number of remaining teeth, periodontal pocket depth, and maximal occlusal force. Associations between MoCA-J scores and occlusal force were investigated via bivariate and multivariate analyses. RESULTS: Education level, financial status, depression score, and intake of green and yellow vegetables, as well as number of teeth and occlusal force, were significantly correlated with MoCA-J scores in both age groups. Among individuals aged 80 years, CRP and periodontal status were weakly but significantly associated with MoCA-J score. After controlling for all significant variables via bivariate analyses, the correlation between maximal occlusal force and cognitive function persisted. A path analysis confirmed the hypothesis that cognitive function is associated with occlusal force directly as well as indirectly via food intake. CONCLUSIONS: After controlling for possible factors, maximal occlusal force was positively associated with cognitive function directly as well as indirectly through dietary intake.

A klotho gene single nucleotide polymorphism is associated with the onset of stroke and plasma klotho concentration.

Klotho protects against development of multiple age-related disorders, including cardiovascular diseases. We assessed whether a human klotho single nucleotide polymorphism (SNP) rs650439 is associated with the onset of stroke in hypertensive patients and plasma klotho concentration in the general population. Five hundred and twenty-three patients with hypertension were analyzed for both the presence of rs650439 and onset of stroke. We found that hypertensive patients with the TT genotype of rs650439 (n=52) had a higher incidence of stroke than those with AT (n=257) and AA (n=214) genotypes. Multivariate analysis indicated that the TT genotype was the only risk factor associated with increased incidence of stroke. Plasma klotho concentrations were measured in a general population (age=70±1 years) to assess the association between rs650439 and plasma klotho concentration. A significant trend was observed in the elderly population where plasma klotho concentration decreased as the T alleles in rs650439 increased. Subjects with a TT genotype had lower plasma klotho concentrations than those with AT+AA genotypes. In conclusion, TT genotype of klotho SNP (rs650439) is correlated with an increased incidence of stroke in hypertensive patients, and the mechanism underlying this correlation might involve the effect of rs650439 T allele on plasma klotho concentrations.

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 (ß=-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.

Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice.

The conventional forelimb grip strength test is a widely used method to assess skeletal muscle function in rodents; in this study, we modified this method to improve its variability and consistency. The modified test had lower variability among trials and days than the conventional test in young C57BL6 mice, especially by improving the variabilities in male. The modified test was more sensitive than the conventional test to detect a difference in motor function between female and male mice, or between young and old male mice. When the modified test was performed on male mice during the aging process, reduction of grip strength manifested between 18 and 24 months of age at the group level and at the individual level. The modified test was similar to the conventional test in detecting skeletal muscle dysfunction in young male dystrophic mice. Thus, the modified forelimb grip strength test, with its improved validity and reliability may be an ideal substitute for the conventional method.

Factors associated with the severity of obstructive sleep apnea in older adults.

AIM: Epidemiological studies have shown that severe obstructive sleep apnea (OSA) is associated with higher mortality when compared with mild to moderate OSA. Because aging is a well-known risk factor for OSA, we aimed to elucidate the underlying factors associated with the severity of OSA in elderly patients. METHODS: Patients who underwent polysomnography were divided into the non-elderly group (aged <65 years; n = 44) and the elderly group (aged ≥65 years; n = 46). The severity of OSA was determined by the apnea hypopnea index (AHI), and each group was subdivided into two groups: mild to moderate OSA (5 < AHI < 30) and severe OSA (AHI ≥30) . In the elderly group, geriatric assessments to evaluate physical and neuropsychiatric function were carried out. RESULTS: All patients had OSA as diagnosed by an AHI >5. Whereas body mass index was positively correlated with AHI in both groups, age was correlated with AHI only in the elderly group. Body mass index and age were higher in severe OSA than mild to moderate OSA in the elderly group. Unexpectedly, no significant difference was observed in physical strength, cognitive function, apathy scale, depression scale or activities of daily living between mild to moderate OSA and severe OSA in the elderly group. Binary logistic regression analysis showed that male sex, body mass index and aging were independent risk factors of severe OSA in the elderly group. CONCLUSIONS: Our findings suggest that aging increases the severity of OSA in elderly patients, even if they are physically active and neuropsychiatrically unimpaired. Geriatr Gerontol Int 2017; 17: 614-621.

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.

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 oxLDL-induced 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.

Prognostic impact of regional arterial stiffness in hypertensive patients.

Many reports have shown that brachial-ankle pulse wave velocity (baPWV) and carotid-femoral PWV are prognostic factors for cardiovascular diseases. We evaluated heart-carotid PWV, heart-femoral PWV (hfPWV), and femoral-ankle PWV (faPWV) using carotid and femoral sensors. Our objectives were to reveal correlations among PWVs and to determine the clinical importance of the respective PWVs in predicting the cardiovascular events. This prospective cohort study included 338 patients with essential hypertension (mean age 61.3 ± 0.7, mean follow-up period 6.5 ± 0.1 years) whose regional PWVs were measured. Primary end points were stroke, cardiovascular diseases (CVD), and death. Kaplan-Meier analysis showed that subjects with higher faPWV and baPWV had a significantly higher incidence of stroke (p = 0.0288 and 0.0277, respectively), subjects with higher hfPWV had a significantly higher incidence of CVD (p = 0.0212), subjects with higher baPWV and hfPWV had a significantly higher incidence of stroke + CVD (p = 0.0070 and 0.0463, respectively), and subjects with higher baPWV had a significantly higher mortality rate (p = 0.0367). Cox proportional hazard model revealed that baPWV was a significant risk factor for stroke + CVD after adjustment for traditional risk factors (relative risk: 14.50, p = 0.0288). Higher baPWV may be a risk factor for stroke and CVD, but the prognostic impact of regional PWVs is still unclear in patients with hypertension.

Carotid plaque score and intima media thickness as predictors of stroke and mortality in hypertensive patients.

The mean intima media thickness (IMT) and plaque score from carotid ultrasonography are both widely used to evaluate macrovascular atherosclerotic change. The present study sought to examine which parameter more effectively predicts patient prognosis. This hospital-based cohort study included 356 patients with essential hypertension (mean age: 62.4 ± 0.6). We investigated how the mean IMT and plaque score correlated with various parameters, including pulse wave velocity (PWV), and we assessed the ability of the mean IMT and plaque score to predict cardiovascular events and total mortality. The mean IMT and plaque score significantly correlated with systemic atherosclerotic change, target organ damage, age and PWV. Subjects with a higher mean IMT and subjects with higher plaque scores showed higher frequencies of stroke and total mortality. In addition, subjects with marginal thickening of the intima media (mean ≥ 0.7) showed a significantly higher frequency of stroke than subjects with a mean IMT of <0.7. After adjustment for traditional risk factors, plaque score was significantly and independently predictive of stroke, and the predictive ability of the plaque score for the onset of stroke was equivalent to that of PWV. The mean IMT and plaque score showed a nonsignificant trend of higher risk of mortality after adjustment for traditional risk factors. The mean IMT and plaque score were significantly correlated with systemic atherosclerotic change. We revealed that plaque score predicted the onset of stroke more accurately than the mean IMT, and the accuracy of this prediction was equivalent to that from PWV in hypertensive patients. We also showed that marginal thickening of the intima media (as measured by mean IMT) may be a predictor of stroke.

Loss of ACE2 exaggerates high-calorie diet-induced insulin resistance by reduction of GLUT4 in mice.

ACE type 2 (ACE2) functions as a negative regulator of the renin-angiotensin system by cleaving angiotensin II (AII) into angiotensin 1-7 (A1-7). This study assessed the role of endogenous ACE2 in maintaining insulin sensitivity. Twelve-week-old male ACE2 knockout (ACE2KO) mice had normal insulin sensitivities when fed a standard diet. AII infusion or a high-fat, high-sucrose (HFHS) diet impaired glucose tolerance and insulin sensitivity more severely in ACE2KO mice than in their wild-type (WT) littermates. The strain difference in glucose tolerance was not eliminated by an AII receptor type 1 (AT1) blocker but was eradicated by A1-7 or an AT1 blocker combined with the A1-7 inhibitor (A779). The expression of GLUT4 and a transcriptional factor, myocyte enhancer factor (MEF) 2A, was dramatically reduced in the skeletal muscles of the standard diet-fed ACE2KO mice. The expression of GLUT4 and MEF2A was increased by A1-7 in ACE2KO mice and decreased by A779 in WT mice. A1-7 enhanced upregulation of MEF2A and GLUT4 during differentiation of myoblast cells. In conclusion, ACE2 protects against high-calorie diet-induced insulin resistance in mice. This mechanism may involve the transcriptional regulation of GLUT4 via an A1-7-dependent pathway.

Adiponectin single nucleotide polymorphism is a genetic risk factor for stroke through high pulse wave pressure: a cohort study.

AIM: Adiponectin is a key molecule involved in metabolic syndrome. Single nucleotide polymorphisms (SNPs) in the ADIPOQ gene encoding adiponectin correlate with various diseases, such as diabetes mellitus; however, there is insufficient information about ADIPOQ SNPs and the onset of cardiovascular events. METHODS: This hospital-based cohort study included 353 patients with essential hypertension (mean age, 62.9±0.6; mean follow-up period. 7.9±0.2 years) in whom ADIPOQ SNPs encoding G276T, I164T, A349G, and/or G967A amino acid changes were detected. We analyzed the correlation between ADIPOQ SNPs and various parameters, including pulse wave velocity (PWV), and assessed whether these SNPs could be risk factors for the onset of stroke, cardiovascular disease, and mortality. RESULTS: Subjects with the T allele of G276T showed significantly lower HDL cholesterol, and significantly higher HbA1c and brachial-ankle PWV (baPWV). Kaplan-Meier analysis revealed that subjects with the T allele of G276T had a significantly higher frequency of stroke (p= 0.0489). The Cox proportional hazard model showed that the T allele of G276T was an independent and significant risk factor for stroke after adjusting for traditional risk factors (relative risk: 1.879, p= 0.0479); however, when adjusted for traditional risk factors and baPWV, the relative risk was significantly diminished (relative risk: 0.710, p= 0.4937). G276T was significantly correlated with dyslipidemia and glucose metabolism. CONCLUSION: The T allele of G276T was a significant and independent risk for the onset of stroke, and mediated the incidence of stroke through increased arterial stiffness.

-374 T/A polymorphism in RAGE gene is associated with onset of diabetes mellitus, atherosclerosis, and renal dysfunction in patients with hypertension.

Receptor of advanced glycation end products (RAGE) is reportedly linked with chronic inflammatory diseases due to aging or diabetes. The aim of this study was to show how -374 T/A RAGE has an impact on systemic vascular damage and renal function. The study subjects were a total of 468 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study cohort. We prospectively examined the association of -374 T/A RAGE with their prognoses and investigated the correlation between -374 T/A RAGE and multiple clinical parameters. Kaplan-Meier analysis did not show a significant association of -374 T/A RAGE with total mortality or the prevalence of cardiovascular events. Carriers of the A allele showed a significantly higher prevalence of diabetes mellitus (DM) and lower estimated glomerular filtration rate (eGFR) than subjects without this allele. In subjects with DM, carriers of the A allele showed a significantly lower eGFR. These significant correlations were only seen in male subjects. Carriers of the A allele of -374 T/A RAGE show an independent risk of atherosclerosis and reduced renal function in male hypertensive patients with DM.

Relationship between renal hemodynamic status and aging in patients without diabetes evaluated by renal Doppler ultrasonography.

BACKGROUND: Aging is well known as one of the major causes of a reduced glomerular filtration rate (GFR). The resistive index (RI) measured by renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance induced by arteriosclerosis. In this study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage or the mechanisms of reduction of renal function by aging. METHODS: We investigated the correlation between RI and multiple clinical parameters and the influence of aging on the renal hemodynamic status of 194 in-patients (mean age 66.2 years) who underwent RDU at our hospital between February 2009 and July 2010. RESULTS: RI was significantly correlated with the age, estimated GFR (eGFR), diastolic blood pressure, pulse pressure, and degree of albuminuria. Subjects aged ≥75 years showed a significantly higher correlation coefficient between eGFR and RI. RI showed a stronger correlation with age in subjects aged ≥75 years compared to eGFR. CONCLUSION: The present study showed that renal vascular resistance and intra-renal arteriosclerosis had a greater impact on renal function in older than younger subjects, reflecting the possible mechanisms of renal function reduction due to aging.

A single nucleotide polymorphism of the adenosine deaminase, RNA-specific gene is associated with the serum triglyceride level, abdominal circumference, and serum adiponectin concentration.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the adenosine deaminase, RNA-specific (ADAR) gene were reported to be associated with human longevity. There are possibilities that ADAR is associated with major risk factors of atherosclerotic cardiovascular diseases (CVD), such as hypertension, diabetes, dyslipidemia, and obesity. OBJECTIVE: To investigate the association between SNPs of the ADAR gene and clinical data associated with major risk factors of atherosclerotic CVD. SUBJECTS: A total of 1504 general population residents (586 males and 918 females) of two towns, Tanno-cho and Sobestu-cho, in Hokkaido, Japan. METHODS: Clinical data associated with risk factors of atherosclerotic CVD were collected from these study subjects. DNA from peripheral blood and written informed consent were obtained. Three single nucleotide polymorphisms of ADARB1 and ADARB2, which were previously reported to be associated with longevity, were genotyped employing the TaqMan PCR method. The associations between SNPs in ADARB1 and ADARB2 and clinical parameters related to risk factors of atherosclerosis were analyzed. RESULTS: On uni- and multivariate analyses, rs2805533 in ADARB2 was significantly associated with the abdominal circumference, body mass index, serum triglyceride level, and serum adiponectin level. The subjects with the AA genotype of rs2805533 had a greater abdominal circumference, higher body mass index, higher triglyceride level, and lower adiponectin level than those with AG and GG genotypes. CONCLUSION: The SNP in ADARB2 related to longevity is associated with metabolic disorders. This finding suggests that genetic factors modulate human longevity via the regulation of metabolic factors such as abdominal obesity and lipid profiles.

The impact of visit-to-visit variability in blood pressure on renal function.

Hypertension is an important risk factor for cardiovascular diseases such as chronic kidney disease. It is still not fully understood how blood pressure impacts the kidneys. In this study, we aimed to establish the significance of visit-to-visit variability in blood pressure for renal function. We analyzed 143 consecutive patients undergoing renal Doppler ultrasonography in our hospital ward and measured blood pressure at outpatient visits six or more times. We analyzed the correlation between visit-to-visit variability in blood pressure and multiple clinical parameters, including albuminuria and resistive index evaluated by renal Doppler ultrasonography, which is thought to be a good indicator of renal vascular resistance. Subjects with higher variability in systolic blood pressure showed a significantly higher prevalence rate of clinical albuminuria and microalbuminuria, and showed significantly higher resistive index. Stepwise multiple regression analysis showed that variability in systolic blood pressure was a significant risk factor for higher resistive index, independent of other renal risk factors. Visit-to-visit variability in blood pressure correlates significantly with renal function and renal arteriosclerotic change. This parameter could provide additional information about renal arteriosclerotic change independent of estimated glomerular filtration rate and albuminuria, and should be considered a therapeutic target for renal protection.

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population.

Heart failure with preserved ejection fraction is recently highlighted as a major health problem, and diastolic dysfunction associated with hypertension has a dominant role in the development of heart failure with preserved ejection fraction. Osteopontin (OPN) is a secreted phosphoprotein, which mediates fibrosis. In animal models, OPN is upregulated in response to pressure overload and is thought to be involved in systolic dysfunction. However, the functional role of OPN in diastolic dysfunction is unknown. The guanine base insertion polymorphism at -156 position of the OPN promoter is postulated to upregulate the transcription of OPN in human. To investigate whether -156del/G polymorphism of OPN promoter is associated with diastolic dysfunction in hypertensive hearts, the patients with hypertension have been genotyped for variants of -156del/G polymorphism by genomic sequencing. Diastolic function of the left ventricle was estimated as the ratio of early to atrial filling (E/A ratio), obtained by pulsed-Doppler derived transmitral flow in echocardiographic analysis. The patients with -156G allele displayed lower E/A ratio compared with those with -156del/del genotype, suggesting exacerbated diastolic function. Notably, in case of the population with diabetes mellitus, the patients with -156G allele showed significant association with lower E/A ratio, compared with -156del/-156del patients. Multiple linear regression analysis revealed that prevalence of -156G allele was an independent factor for lowering E/A ratio. The -156del/G genetic variants of OPN promoter were associated with decreased E/A ratio in hypertensive patients. These results suggest that OPN has a functional role in the development of diastolic dysfunction in hypertensive hearts.

Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.

AIM: Mice that carry the Klotho mutation (KL(-) (/) (-) ) manifest diverse age-related disorders similar to those observed in humans. Thus, the Klotho protein might function as an anti-aging hormone in mammals. Recently, we reported that Klotho recombinant protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal-regulated kinase and mitogen-activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence. METHODS: Cellular senescence was investigated in human umbilical vein endothelial cells treated with or without Klotho recombinant protein, and with or without inhibitors of mitogen-activated kinases. Senescence was quantified by staining with senescence-associated ß-galactosidase and by evaluating western blots probed for phosphorylation of mitogen-activated kinases. Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9. RESULTS: The Klotho recombinant protein induced transient phosphorylation of mitogen-activated kinases within a few minutes. Application of inhibitors of mitogen-activated kinases attenuated the ability of Klotho to interfere with apoptosis and senescence in endothelial cells. CONCLUSION: This study demonstrated that Klotho attenuated cellular apoptosis and senescence in vascular cells via mitogen-activated kinase kinase and extracellular signal-regulated kinase pathways.