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Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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Background Night eating has been associated with an elevated risk of obesity, dyslipidemia, and cardiovascular disease. However, there is no longitudinal study on whether habitual night eating, regardless of diet quality and energy intake, is associated with arterial stiffness, a major etiological factor in the development of cardiovascular disease. Methods and Results The study included 7771 adult participants without cardiovascular disease, cancer, or diabetes mellitus prior to dietary assessment by a validated food frequency questionnaire in 2014 through 2015. Participants were categorized into 3 groups based on self-reported night-eating habits: never or rarely, some days (1-5 times per week), or most days (6+ times per week). Arterial stiffness was assessed by brachial-ankle pulse wave velocity at baseline and repeatedly during follow-ups. Mean differences and 95% CIs in the yearly change rate of brachial-ankle pulse wave velocity across the 3 groups were calculated, adjusting for age, sex, socioeconomic status, total energy intake, diet quality, sleep quality, and other cardiovascular disease risk factors. At baseline, 6625 (85.2%), 610 (7.8%), and 536 (6.9%) participants reported night eating as never or rarely, some days, or most days, respectively. During a mean 3.19 years, we observed a positive association between night-eating frequency and progression of arterial stiffness ( P trend=0.01). The adjusted difference in brachial-ankle pulse wave velocity change rate between the group that ate at night most days and the group that never or rarely ate at night was 14.1 (95% CI, 0.6-27.5) cm/s per year. This association was only significant in women, but not in men ( P interaction=0.03). Conclusions In an adult population free of major chronic diseases, habitual night eating was positively associated with the progression of arterial stiffness, a hallmark of arteriosclerosis and biological aging. Registration URL: https://www.chictr.org.cn; Unique identifier: ChiCTR-TNRC-11001489.

Background: Hypertension is a major modifiable risk factor for arteriosclerosis that can lead to target organ damage (TOD) of heart, kidneys, and peripheral arteries. A recent epigenome-wide association study for blood pressure (BP) identified 13 CpG sites, but it is not known whether DNA methylation at these sites is also associated with TOD., Methods: In 1218 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a cohort of hypertensive sibships, we evaluated the associations between methylation at these 13 CpG sites measured in peripheral blood leukocytes and five TOD traits assessed approximately 5 years later., Results: Ten significant associations were found after adjustment for age, sex, blood cell counts, time difference between CpG and TOD measurement, and 10 genetic principal components (FDR q < 0.1): two with estimated glomerular filtration rate (eGFR, cg06690548, cg10601624), six with urinary albumin-to-creatinine ratio (UACR, cg16246545, cg14476101, cg19693031, cg06690548, cg00574958, cg22304262), and two with left ventricular mass indexed to height (LVMI, cg19693031, cg00574958). All associations with eGFR and four associations with UACR remained significant after further adjustment for body mass index (BMI), smoking status, and diabetes. We also found significant interactions between cg06690548 and BMI on UACR, and between 3 CpG sites (cg19693031, cg14476101, and cg06690548) and diabetes on UACR (FDR q < 0.1). Mediation analysis showed that 4.7% to 38.1% of the relationship between two CpG sites (cg19693031 and cg00574958) and two TOD measures (UACR and LVMI) was mediated by blood pressure (Bonferroni-corrected P < 0.05). Mendelian randomization analysis suggests that methylation at two sites (cg16246545 and cg14476101) in PHGDH may causally influence UACR., Conclusions: In conclusion, we found compelling evidence for associations between arteriosclerotic traits of kidney and heart and previously identified blood pressure-associated DNA methylation sites. This study may lend insight into the role of DNA methylation in pathological mechanisms underlying target organ damage from hypertension.

Background: Arteriosclerosis can be reflected in various aspect of the artery, including atherosclerotic plaque formation or stiffening on the arterial wall. Both arteriosclerosis and atherosclerosis are important and closely associated with cardiovascular disease (CVD). The aim of the study was to evaluate the association between systemic arteriosclerosis and multi-site atherosclerotic plaques., Methods: The study was designed as an observational cross-sectional study. A total of 1178 participants (mean age 67.4 years; 52.2% male) enrolled into the observational study from 2010 to 2017. Systemic arteriosclerosis was assessed by carotid femoral artery pulse wave velocity (CF-PWV) and multi-site atherosclerotic plaques (MAP, > = 2 of the below sites) were reflected in the carotid or subclavian artery, abdominal aorta and lower extremities arteries using ultrasound equipment. The associations were assessed by multivariable logistic regression., Results: The prevalence of CF-PWV > 12 m/s and MAP were 40.2% and 74.4%. Atherosclerotic plaques in 3 sites were more common in male compared with that in female (48.9% versus 36.9%, p < 0.05). All CVD factors were worse in participants with MAP than that with <=1 site. Participants with CF-PWV > 12 m/s corresponded to a mean 82% probability of MAP with age and sex-adjusted. Patients with peripheral artery disease showed the highest odds ratio (OR) (3.88) for MAP, followed by smoking (2.485), CF-PWV > 12 m/s (2.25), dyslipidemia (1.89), male (1.84), stroke (1.64), hypoglycemic agents (1.56) and age (1.09) (all p < 0.001)., Conclusions: MAP was highly prevalent in this cohort, with male showing a higher prevalence than female. Higher systemic arteriosclerosis was independently associated with MAP, which indicating the supplementary value of arteriosclerosis for the earlier identification and intervention on MAP., Trial Registration: Clinical Trial, URL: http://www.clinicaltrials.gov . Unique identifier: NCT02569268 .

Objective: The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia). Approaches and Results: In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s, P <0.0001), Zc ( P <0.0005), and Pf ( P <0.0001) were higher and early systolic pulse pressure amplification lower ( P <0.0001) in those with precipitous events than in controls. In comparison to age- and sex-matched controls, independent of risk factors, pulse wave velocity, and Zc ( P <0.005 and <0.05) were more closely associated with premature events than events in older persons and Pf and early systolic pulse pressure amplification were at least as closely associated with premature events as events in older persons., Conclusions: Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.

Although several risk factors have been reported for cervical ossification of the longitudinal ligament (OPLL), most evaluations made in the past were based on plain X-ray, not on computed tomography (CT) scan. In this study, we aimed to clarify novel risk factors for cervical OPLL in asymptomatic subjects undergoing CT scan as their routine medical checkups. A total of 1789 Japanese asymptomatic subjects who underwent CT scan for the whole body as their routine medical checkups were retrospectively reviewed. The medical checkup also included laboratory examinations, bone mineral status, and ultrasound of the carotid artery. As a result, cervical OPLL was seen in 120 subjects (6.7%). As we compared the demographic and clinical data between subjects with and without OPLL, OPLL group showed older age, higher proportion of male sex, higher BMI, higher incidence of hypertension, higher levels of blood HbA1c and triglyceride, and higher incidence of plaques in the carotid artery. A multivariate logistic regression analysis revealed that age (Odds ratio (OR):1.03), male sex (OR: 1.91), and the presence of plaque in the carotid artery (OR: 1.71) were risk factors for OPLL. To the best of our knowledge, this is the first report to reveal an association between OPLL and arteriosclerotic lesions.

Background: Endovascular treatment offers an alternative, less invasive approach to open repair for subclavian artery atherosclerotic disease (SAAD). However, only few studies compared the outcomes of both strategies in the long run. This study reports on the performance of endovascular and surgical revascularization for SAAD., Methods: A retrospective review was conducted on patients treated for SAAD at two institutions between January 1998 and December 2015. Primary outcome of this study was the composite endpoint of reintervention-free survival (RFS) defined as time to reintervention and/or death from any cause. Secondary endpoints included primary patency (PPR) and secondary patency (SPR) rates as well as overall survival and time to reintervention., Results: Surgical treatment was the preferred treatment option in 27 (25%) patients, while 83 (75%) patients underwent primary stent therapy. The median follow-up was 87 months (interquartile range [IQR]: 38 to 151) in the surgical group and 27 (IQR: 12 to 59) in the endovascular (P=0.0001). Severe arterial wall calcification was more commonly observed in the surgical arm (P<0.0001), while mild and moderate calcification in the endovascular (P=0.0004 and P=0.014). Vessel occlusion was more frequent among patients treated surgically (100% vs. 34%, P<0.0001). At 98 months RFS was significantly higher after surgical treatment (95% vs. 54%, HR: 8.4, 95% CI: 3.9 to 18.1, P=0.0002). Although overall survival did not differ significantly between the two groups (HR: 4.28, 95% CI: 0.86 to 21.22, P=0.093), open repair was associated with reduced reintervention rate (HR: 12.04, 95% CI: 4.98 to 29.12, P=0.001). The PPR at 98 months following surgical and endovascular therapy amounted to 96% and 65% (HR: 12.87, 95% CI: 5.44 to 30.44, P=0.0008) respectively. No significant difference was observed regarding the SPR between the two groups (100% vs. 95%, P=0.090)., Conclusions: Surgical treatment was associated in this cohort with increased patency and a significant reduction of reinterventions compared to the endovascular approach.

Preventing cardiovascular disease (CVD) is an urgent public health challenge. Although brachial-ankle pulse wave velocity (baPWV) can indicate the risk of arterial stiffness and CVD, findings regarding whether baPWV is associated with smoking are inconsistent. This study considered the influence of smoking on arteriosclerosis, specifically focusing on secondhand smoke (SHS), and aimed to construct a strategy for preventing the worsening of arteriosclerosis. We recruited 295 male employees from five companies who had smoking habits such as being smokers, living with smokers, and exposure to SHS outside the home. We measured body composition and hemodynamics, including blood pressure and baPWV, and found that baPWV had significant positive correlations with age, smoking index, alcohol consumption, body-fat percentage, blood pressure, and heart rate, and significant negative correlations with height, fat-free mass, and lower-limb muscle mass. Moreover, baPWV showed a significant adverse effect on participants who had metabolic syndrome (MetS) risk factors such as hypertension, dyslipidemia, and diabetes. Multiple regression analysis showed that baPWV had significant positive relationships with age, height, MetS risk factors, cohabitation with smokers, blood pressure, and heart rate, and a significant negative relationship with lower-limb muscle mass. The same results were obtained when adjusting for current smoking status, smoking index, cohabitation with smokers at birth, and frequency of exposure to SHS outside the home. Exposure to tobacco smoke due to cohabitation with smokers increased baPWV regardless of the person's smoking habits. Thus, to prevent an increase in baPWV in housemates and smokers, it is necessary for smokers to quit smoking.

Objectives: Coronary slow flow phenomenon (CSFP) could be a manifestation of systemic arteriosclerosis, as coronary and carotid arteries have similar intimal thickening. However, as an initial cause of arteriosclerosis, hemodynamic changes in carotid arteries have rarely been studied., Methods: Twenty patients with angiography-proven CSFP and 39 patients with normal coronary flow (NCF) were enrolled. TIMI frame counts (CTFC) were investigated. Carotid intima-media thickness (CIMT), peak systolic velocity (PSV), and end-diastolic velocity (EDV) were measured by ultrasonography, and shear rate (SR) and resistance index (RI) were calculated., Results: The results showed that PSV, EDV, SR, and RI were significantly lower in patients with CSFP (p＜0.01), but CIMT was significantly increased (P ＜ 0.01). PSV, EDV, SR, and RI were negatively correlated with CTFC, while CIMT was positively correlated with CTFC. Logistic regression analysis revealed that PSV (OR = 0.95, P < 0.01) could be an independent protective factor against CSFP, but CIMT (OR = 1.10, P ＜ 0.05) and male gender (OR = 9.89, P ＜ 0.01) could be risk factors for CSFP., Conclusions: The slow flow phenomenon was observed in both coronary and carotid arteries, which could be a characteristic manifestation of systemic arteriosclerosis in CSFP; the lower wall shear stress may be the underlying mechanism. Carotid ultrasound could be applied in the noninvasive diagnosis of CSFP in the future., (© 2019 Wiley Periodicals, Inc.)

BACKGROUND The aim of this study was to investigate the association between body mass index (BMI) and brachial-ankle pulse wave velocity (baPWV) in hypertensive males. MATERIAL AND METHODS Altogether, 14 866 male hypertensive participants were included in the analysis. Participants were divided into 3 groups: low BMI group (BMI <24 kg/m²), moderate BMI group (24 kg/m² ≤BMI <28 kg/m²), and high BMI group (BMI ≥28 kg/m²). According to baPWV values, arteriosclerosis (AS) was set as 3 degrees: mild AS (baPWV ≥1400 cm/s), moderate AS (baPWV ≥1700 cm/s) and severe AS (baPWV ≥2000 cm/s). Multivariate logistic regression analysis was used to explore the effect of different BMI groups on different degrees of AS. The multivariate linear regression analysis was used to explore the relationship between BMI and baPWV. RESULTS Among low BMI, moderate BMI, and high BMI groups, the average baPWV values were 1824±401 cm/s, 1758±363 cm/s, and 1686±341 cm/s, respectively. Prevalence in the mild, moderate and high BMI groups were 91.0%, 87.8%, 81.5%, respectively for mild AS; 55.3%, 48.8%, and 40.0% respectively for moderate AS; and 25.9%, 20.2%, and 14.9% respectively for severe AS. Compared to the low BMI group, multivariate logistic regression analysis showed that odds ratio (OR) and 95% confidence intervals (95%CI) in the moderate BMI group and the high BMI were 0.71 (95%Cl, 0.62-0.80), 0.43 (95%Cl, 0.38-0.50) for mild AS; and similar trends were shown for moderate AS and severe AS. Based on age-stratification, a negative relationship remained for 35-55 years old participants for different degrees of AS among the moderate BMI group and the high BMI group. A negative relationship was detected between BMI and baPWV in total and different age-stages. CONCLUSIONS Among male hypertension participants in this study, there was a negative relationship between BMI and baPWV. High BMI was found to be a protective factor for AS especially in the age range of 35-55 years.

Objective: Aortic calcification (AC) is associated with increased risks of cardiovascular events and mortality. Numerous studies have explored the association between calcification and abdominal artery aneurysm. However, evidence regarding the association between AC and acute aortic dissection (AAD) is limited. We aimed to evaluate the association between AC-related variables and the development of intimal tear (IT) in patients with AAD., Methods: We conducted a retrospective observational study involving 64 patients with type A AAD and 32 patients with type B AAD from February, 2011 to January, 2017 at a tertiary referral medical center in Taiwan. We used the default analysis module "calcification score analysis" to calculate all the calcification variables, including AC scores and volume., Results: We identified an association between AC and AAD. Patients with AAD had a greater AC volume in the aortic arch and greater AC scores for both the ascending aorta and the aortic arch than did patients without AAD. However, hypertension and coronary artery disease, rather than AC remained to be the independent risk factor for AAD in multivariate analysis. Patients with type A AAD had greater mean and cumulative AC volumes in the aortic arch, greater cumulative AC volumes in the whole aorta and higher cumulative AC scores in the aortic arch than did patients with type B AAD. ACs were superimposed on ITs in nearly half of the patients with AAD. In patients with type A AAD, AC was more commonly located distal to the IT and farther from the IT., Conclusions: We identified the associations between AC-related variables and the location of IT in patients with AAD. However, AC was not an independent risk factor for AAD. The distribution of AC was different between patients with type A and type B AAD., Competing Interests: The authors have declared that no competing interests exist.

Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Background: Renal resistive index (RI) calculated using renal Doppler ultrasonography (RDU) has recently been considered a clinically important indicator of renal outcome, survival, and systemic arteriosclerotic disorders. However, the cause of RI elevation remains unclear. The present study was an effort to first, identify the factors related to RI elevation, and second, understand the effect of renin-angiotensin system inhibitors (RAS-Is) on renal RI elevation., Methods: We carried out this single-center case-control study among 100 CKD patients, recruited from outpatients who underwent RDU more than twice, at least a year apart. The rate of renal RI change per year (dRIpy) was chosen as the dependent variable: [(last examined renal RI-initial examined renal RI)/(initial examined renal RI × period of observation) × 100 (%/year)]. We examined the association between dRIpy and other clinical and biological data., Results: Among 100 CKD patients, the average serum creatinine and eGFR were 1.76 ± 0.84 mg/dL and 37.0 ± 18.2 ml/min/1.73 m 2 , respectively. The average dRIpy in all patients was 1.8 ± 1.4%/year. The linear multiple regression demonstrated that dRIpy was positively associated with the presence of diabetes mellitus (DM) and high low-density lipoprotein cholesterol (LDL) levels, and negatively with eGFR and RAS-I use., Conclusions: This study demonstrated that the elevation of RI was related to DM, eGFR, high LDL, and the use of RAS-Is. In particular, RAS-Is could contribute towards suppressing the elevation of RI in CKD patients and towards preventing the development of renal failure in CKD patients.

To develop a risk chart or score that is based on recent data and applicable to the Japanese people, we need a large cohort study representative of the Japanese people without a need for long-term follow-up. The purpose of the present study was to develop a risk scoring system to estimate the 5- and 10-year absolute and cumulative incidence risk of stroke and acute myocardial infarction (AMI), composite outcome of stroke and AMI, and death from all cardiovascular disease (CVD). The cumulative incidence risk ratios were calculated using a multiple Poisson regression model and data from the Japan Arteriosclerosis Longitudinal Study, which included 67,969 men and women aged 40-89 years. An absolute risk scoring system for 5- and 10-year risk was developed. For blood pressure categories, the risk ratios for all outcomes increased from normal blood pressure (systolic blood pressure (SBP) 120-129 mmHg and diastolic blood pressure (DBP) 80-89 mmHg) to grade III hypertension (SBP ≥ 180 and/or DBP ≥ 110) based on the 2014 Guidelines for the Management of Hypertension compared to the reference optimal blood pressure (SBP < 120 and DBP < 80). Grade II (SBP 160-179 and/or DBP 100-109) and III hypertension treated with medication showed a lower risk compared to counterparts without medication. Other risk factors showed reasonable figures. The total of scores for each risk factor indicated the estimated absolute risk for stroke and AMI, the composite outcome of stroke and AMI, and all CVD. This scoring system may contribute to patient education and to the development of strategies for reducing CVD in the population.

This paper proposes an algorithm for estimating the arterial viscosity using cuff pressures and pulse waves measured by an automatic oscillometric sphygmomanometer. A change in the arterial viscosity during the enclosed-zone flow-mediated dilation test is calculated as an index for evaluating the vascular endothelial function %η. In all, 43 individuals participated in this study. After the index %η was calculated, the accuracy of the index %η in distinguishing healthy subjects and subjects at a high risk of arteriosclerosis was tested via a receiving operating characteristic (ROC) analysis. The calculated %η for the healthy participants and those at a high risk of arteriosclerosis was 13.4 ± 55.1% and -32.7 ± 34.0% (mean ± S.D.), respectively. The area under the ROC curve was 0.77. Thus, it was concluded that the proposed method can be used to evaluate the vascular endothelial function.

Objective Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both complicated by arteriosclerosis, resulting in increased rates of cardiovascular events. No previous studies have compared the index between RA and T2DM. We assessed the vascular endothelial function in early-stage arteriosclerosis for each disease to determine the influential factors and compared the extent to which these two diseases cause vascular endothelial dysfunction. Methods This study is a retrospective study based on medical records. Differences in the reactive hyperemia index (RHI) among the groups and factors affecting the RHI in each group was analyzed. The vascular endothelial function was assessed by measuring the RHI using peripheral arterial tonometry. Patients The study subjects were 114 patients with non-functional thyroid tumors (healthy n=14), T2DM (T2DM n=64), and RA (RA n=36). Results The RHI was 2.29 in the control, 1.85 in the T2DM, and 1.83 in the RA group, with values lower in the T2DM and RA groups than in the control group (p=0.033) but not markedly different between the two disease groups. The RHI distribution (<1.68/1.68 to <2.10/≥2.1) was as follows: control group: 14.3%/28.6%/57.1%; T2DM group: 42.2%/39.1%/18.8%; and RA group: 36.1%/44.4%/19.4% (p=0.031), respectively. A multivariate analysis identified the triglyceride level and dyslipidemia in the control group and the Disease Activity Score in 28 joints with the erythrocyte sedimentation rate and fasting plasma glucose level in the RA group to influence the RHI. Conclusion The vascular endothelial function was impaired in approximately 80% of patients with T2DM and RA, with comparable degrees of impairment between the two diseases. No factors affecting the function were identified in the T2DM group, while the function was more impaired in patients with a higher disease activity in the RA group.

Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, N ω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk., (© 2019 The Authors. International Journal of Experimental Pathology © 2019 International Journal of Experimental Pathology.)

An automated method for measuring arterial path length with devices that determine pulse wave velocity (PWV) in peripheral arteries is frequently applied. We aimed to compare arterial path length measurements based on mathematical height-based formulas with those measured manually and to assess whether the ankle-brachial difference (abD-PWV) measured with the VOPITB device is comparable to that obtained by manual measurements. In 245 patients, a metric measuring tape was used to determine the arterial path length from the suprasternal notch to the midpoint of the VOPITB cuffs wrapped around the extremities, and the results were compared with those obtained with height-based formulas. We examined the relationship between the abD-PWV measured with both methods. The arterial path length measured manually was shorter than that calculated automatically by 5 ± 2 and 30 ± 4 cm-of 13% and 21% for the arms and legs, respectively (difference of 13% and 21%). As a result, the abD-PWV calculated with the automatic method was greater (automatic abD-PWV vs. manual: 462 ± 90 vs. 346 ± 79 cm/s). The Blant Altman plot showed a percentage error of: 15,2%, 7,5% and 17,3% for heart-brachial, heart-ankle length and abD-PWV respectively. In conclusion there were significant differences between manual and automated arterial length measurements and it translates into difference abD-PWV calculate from both methods. However, the Bland-Alman plot showed that abD-PWV was comparable for both techniques. The advantages of height-based formulas for the calculation of arterial path lengths suggest that they may be the recommended method for measuring the abD-PWV., Competing Interests: Juan F Sánchez Muñoz-Torrero has property rights over the patented VOPITB invention (Oficina Española de Patentes y Marcas; number of concession: P201130872; publication number: 2400134) and consultant for MSD, Astra, Pfizer, Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Intrarenal renin-angiotensin system (RAS) activation plays an important role in the development of hypertension and renal damage. However, the association between daytime and night-time intrarenal RAS activation and renal structural damage in normotensive IgA nephropathy patients is unclear. We investigated the relationships between urinary angiotensinogen (U-AGT) excretion, which reflects intrarenal RAS activity, and renal structural damage (i.e., endocapillary and mesangial cell hypercellularity, arteriolar hyalinosis and arteriosclerosis levels, and global glomerulosclerosis and tubulointerstitial fibrosis percentages) in 27 normotensive IgA nephropathy patients (age 39.2 ± 13.6 years, 10 men and 17 women, estimated glomerular filtration rate (eGFR) 74.0 ± 17.3 ml/min/1.73 m 2 , urinary protein excretion 0.58 ± 0.50 g/day, and U-AGT excretion 64.9 ± 100.6 μg/day). The arteriosclerosis level had a significant positive association with the daytime and night-time U-AGT excretion levels. By contrast, the endocapillary and mesangial cell hypercellularity and arteriolar hyalinosis levels and global glomerulosclerosis and tubulointerstitial fibrosis percentages did not correlate with the daytime and night-time U-AGT excretion levels. The daytime and night-time U-AGT excretion levels were higher in patients with arteriosclerotic changes than in patients without these changes. Multiple linear regression analysis revealed that the arteriosclerosis levels had a significant positive association with the U-AGT excretion levels at night after adjusting for age, sex, body mass index, and the eGFR. However, when diastolic BP was added as an independent variable, the relationship between U-AGT excretion and arteriosclerosis at night disappeared. In normotensive IgA nephropathy patients, intrarenal RAS activation at night due to nocturnal hypertension may be associated with arteriosclerosis.

Arterial stiffness is an important risk factor for cardiovascular morbidity and mortality in patients with end-stage renal disease (ESRD). Arterial stiffness aggravates cardiovascular risk via multiple pathways, such as augmentation of aortic systolic pressure, subendocardial hypoperfusion, and excess pulsatile energy transmission from macro- to microcirculation. Pathogenesis of the arteriosclerotic process in ESRD is complex and not yet fully understood. Several factors unique to ESRD, such as mineral metabolism disturbances, vascular calcifications, formation of advanced glycation end-products, and acute and chronic volume overload, are proposed to play a particular role in the progression of arteriosclerosis in ESRD. As these and other mechanistic pathways of arterial stiffening in ESRD are elucidated, there is hope that this knowledge will be translated into novel therapeutic interventions targeting arterial stiffness. In the meantime, blood pressure (BP) lowering via strict volume control and appropriate use of antihypertensive drugs is a fundamental step in reversing accelerated arterial stiffening and modifying the cardiovascular risk profile of ESRD patients. In this article, we review the pathogenesis, clinical epidemiology, and therapies targeting arterial stiffness in ESRD, discussing recent advances and high-priority goals of future research in these important areas.

Background and Aims: Carotid artery longitudinal wall motion (CALM) is a new biomarker, which can be measured together with carotid intima-media thickness and distensibility measurements in the same session. Our objective was to study the relationship between these indicators of vascular health and cardiovascular risk factors in a large and well-characterized study population., Methods: The study population consisted of 465 subjects aged 30-45 years. Successful measurements were performed in 287 participants., Results: The peak-to-peak and retrograde amplitudes of the longitudinal motion were inversely correlated with systolic blood pressure (SBP; r = -0.152, p<0.05 and r = -0.189, p<0.01), diastolic blood pressure (DBP; r = -0.170, p<0.01 and r = -0.256, p<0.001) and body mass index (BMI; r = -0.158, p<0.01 and r = -0.291, p<0.001). In addition, retrograde amplitude of longitudinal motion indirectly correlated with total cholesterol and triglycerides (r = -0.163, p<0.01 and r = -0.228, p<0.001, respectively). Amplitude of antegrade longitudinal motion was directly correlated with DBP, total cholesterol, LDL-cholesterol, triglycerides and BMI (r = 0.198-0.274, p<0.001 for all). Antegrade longitudinal motion increased and retrograde longitudinal motion decreased with the increasing number of cardiovascular risk factors., Conclusions: The magnitude of correlation coefficients between CALM parameters and risk factors was comparable with those for carotid intima-media thickness and distensibility. However, the correlation profile for various risk factors was different and CALM gives additional information regarding arteriosclerosis and risk factors., (Copyright © 2018. Published by Elsevier B.V.)

Background and Objective: In this study, the interaction of pulsatile blood flow with the viscoelastic walls of the axisymmetric artery is numerically investigated for different severities of stenosis. The geometry of artery is modeled by an axisymmetric cylindrical tube with a symmetric stenosis in a two-dimensional case. The effects of stenosis severity on the axial velocity profile, pressure distribution, streamlines, wall shear stress, and wall radial displacement for the viscoelastic artery are also compared to the elastics artery. Furthermore, the effects of atherosclerosis and polycythemia diseases on the hemodynamics and the mechanical behavior of arterial walls are investigated., Methods: The pulsatile flow of non-Newtonian blood is simulated inside the viscoelastic artery using the COMSOL Multiphysics software (version 5) and by employing the fluid-structure interaction (FSI) method and the arbitrary Lagrangian-Eulerian (ALE) method. Moreover, finite element method (FEM) is used to solve the governing equations on the unstructured grids. For modeling the non-Newtonian blood fluid and the viscoelastic arterial wall, the modified Casson model, and generalized Maxwell model are used, respectively., Results: According to the results, with stenosis severity increasing from 25% to 75% at the time of maximum volumetric flow rate, the maximum value of axial velocity and its gradient increase 7.9 and 19.6 times, and the maximum wall shear stress of viscoelastic wall increases 24.2 times in the constriction zone. With the progression of the atherosclerosis disease (fivefold growth of arterial elastic modulus), the wall radial displacement of viscoelastic arterial walls decreases nearly 40%., Conclusions: In this study, axial velocity profile, pressure distribution, streamlines, wall radial displacement, and wall shear stress were examined for different percentages of stenosis (25%, 50%, and 75%). The atherosclerosis disease was investigated by the fivefold growth of viscoelastic arterial elastic modulus and polycythemia disease was examined by the 21-fold increase in the yield stress of the blood fluid. Furthermore, the comparison of results between the elastic and viscoelastic arterial walls shows that the wall radial displacement for viscoelastic artery is lower than that for the elastic artery as much as 21.7% for the severe stenosis of 75%., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events, with this effect postulated to be due to its effect on cardiac afterload, atherosclerosis (plaque formation) progression or both, but with limited evidence examining these early in disease formation. The aim of the current study is to examine the association between arteriosclerosis, atherosclerosis and ventricular remodelling in a population at low-intermediate cardiovascular risk., Methods: One thousand six hundred fifty-one subjects free of clinical cardiovascular disease and with a < 20% 10 year cardiovascular risk score underwent a cardiovascular magnetic resonance (CMR) study and whole body CMR angiogram. Arteriosclerosis was measured using total arterial compliance (TAC) - calculated as the indexed stroke volume divided by the pulse pressure. Atherosclerosis was quantified using a standardised atheroma score (SAS) which was calculated by scoring 30 arterial segments within the body based on the degree of stenosis, summating these scores and normalising it to the number of assessable segments. Left ventricular remodelling was measured using left ventricular mass to volume ratio (LVMVR)., Results: One thousand five hundred fifteen (38% male, 53.8 ± 8.2 years old) completed the study. On univariate analysis TAC was associated with SAS but this was lost after accounting for cardiovascular risk factors in both males (B = - 0.001 (- 0.004-0.002),p = 0.62) and females (B = 0.000(95%CI -0.002--0.002),p = 0.78). In contrast compliance correlated with LVMVR after accounting for cardiovascular risk factors (B = - 0.12(95%CI -0.16--0.091),p < 0.001 in males; B = - 0.12(95%CI -0.15--0.086),p < 0.001 in females)., Conclusion: Systemic arteriosclerosis is associated with left ventricular remodelling but not atherosclerosis. Future efforts in cardiovascular risk prevention should thus seek to address both arteriosclerosis and atherosclerosis individually.

Background: Elevated serum low-density lipoprotein cholesterol (LDL-C) concentration is a risk factor for atherosclerosis, which involves remodelling of the arterial walls with their subsequent stiffening., Aim: We sought to evaluate the relationship between serum lipid levels and the elastic properties of the arterial wall., Methods: The study group comprised 315 men and women aged 55.84 ± 9.44 years. Serum glucose and lipid concentrations were determited. All subjects underwent blood pressure (BP) measurement, transthoracic echocardiography, and assessment of vascular compliance of large (C1) and small arteries (C2) using the HDI/Pulse Wave™ CR-2000 Research CardioVascular Profiling System (Hypertension Diagnostics Inc., Eagan, MN, USA). The subjects were divided into three groups: group I - LDL-C < 2.6 mmol/L, group II - LDL-C ≥ 2.6 mmol/L and < 4.0 mmol/L, and group III - LDL-C ≥ 4.0 mmol/L., Results: There were no intergroup differences with regard to smoking status (p = 0.56), serum glucose concentration (p = 0.13), body mass index (p = 0.96), systolic (p = 0.17) and diastolic BP (p = 0.29), or C1 (p = 0.09). However, C2 was higher in groups I and II than in group III (5.12 ± 2.57 vs. 5.18 ± 2.75 vs. 4.20 ± 1.58 mL/mmHg × 100, respectively, p < 0.01). Multivariate regression analysis negated the independent associations between C1 and serum lipid levels. In contrast, C2 was independently inversely associated with serum LDL-C concentration (r = -0.15, p < 0.01)., Conclusions: Higher serum LDL-C concentration seems to contribute independently to stiffening of small arterial vasculature in otherwise healthy adults. Screening for dyslipidaemia in the general population and its prompt treatment are highly recom-mended.

In this study, we evaluated the hemodynamics of carotid artery models with carotid bulbs of various sizes using computational fluid dynamics (CFD) and the Fluent CFD software. The oscillatory shear index (OSI) and flow velocity distribution were evaluated in carotid models without a carotid bulb and with carotid bulbs of known geometry (major axis of 10, 11, 12, 13, and 14 mm; carotid bifurcation angle of 50°). Furthermore, the diameters of the common carotid artery, the external carotid artery, and the internal carotid artery were defined as 7.2, 4.0, and 4.5 mm, respectively. The accuracy of the CFD analysis in this study was verified using a flow phantom and measuring velocities with phase-contrast cine magnetic resonance imaging. The CFD parameters were defined as follows: rigid and no-slip walls, pulsatile flow, and 0 Pa of peripheral pressure. The OSI in the carotid bulb tended to show a high value during the expansion of the carotid bulb (maximum and minimum OSI: 0.11 ± 0.08 at d bulb : 14 mm; 0.0013 ± 0.0011 at no bulb), and the region of high OSI expanded with the expansion of the carotid bulb. The flow separated near the carotid bulb, and the flow deceleration expanded downstream as the size of the bulb increased. These findings suggest that the size of the carotid bulbs contributed to the OSI because the larger bulbs exhibited higher OSI values. The relation between the OSI and the carotid bulb size could serve as a risk indicator for atherosclerosis.

Background and Aims: Early diagnosis of arteriosclerosis is fundamental for the prevention of cardiovascular morbidity and mortality. The current study was performed to identify major predictors of arteriosclerosis and to assess the association between arterial stiffness as measured by cardio-ankle vascular index (CAVI) and muscle mass deficit (MMD) estimated by bioelectrical impedance analysis (BIA) in middle-aged men., Methods and Results: Data were gathered from 3356 middle-aged men who visited a health promotion center. CAVI was measured as an index of arterial stiffness. Body composition analysis was performed using BIA. MMD was positively associated with CAVI in the regression model. The odds ratios for high-CAVI (≥9.0) rose with MMD grade in a dose-dependent manner after adjusting for age, lifestyle factors and current medication use. The estimated mean CAVI rose as MMD grade increased (P for trend >0.001)., Conclusions: MMD estimated from BIA was positively associated with arterial stiffness in middle-aged men. These findings show a close interaction between low muscle mass and cardiovascular risk., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

To compare central and brachial blood pressure (BP) in the association of target organ damage (TOD) in a community-based elderly population, 1599 (aged 71.4 ± 6.1 years) participants in northern Shanghai were recruited. TOD included left ventricular hypertrophy (n = 1556), left ventricular diastolic dysfunction (n = 1524), carotid plaque (n = 1558), arteriosclerosis (n = 1485), and microalbuminuria (n = 1516). Both central and brachial BP significantly correlated with TOD. In full-model regression, central BP was significantly associated with all TOD (P ≤ .04), whereas brachial BP was only significantly associated with left ventricular hypertrophy and arteriosclerosis (P ≤ .01). Similarly, in stepwise regression, central BP was significantly associated with left ventricular hypertrophy, left ventricular diastolic dysfunction, arteriosclerosis, and microalbuminuria (P ≤ .04), while brachial BP was not associated with any TOD. Receiver operating characteristic analyses indicated that central BP identified arteriosclerosis and microalbuminuria better than brachial BP (P ≤ .01). In conclusion, central BP showed superiority over brachial BP in the association of hypertensive TOD in a community-based elderly population., (©2017 Wiley Periodicals, Inc.)

Abnormal blood pressure (BP) variability (BPV), occurring as beat-to-beat, 24 h, and day-to-day fluctuations, is related to target organ damage. However, the associations between abnormal BPV and renal structural changes have not been clearly investigated. We evaluated the day time and night time BP s.d. and average real variability (ARV), which reflected short-term BPV, the night time to day time (N/D) ratio of systolic BP (SBP), and the 7-day BPV, in 29 normotensive IgA nephropathy (IgAN) patients. We further compared the results with renal structural changes. The degree of arteriosclerosis was positively correlated with age, s.d. of night time SBP and the N/D ratio of SBP, and was negatively correlated with the estimated glomerular filtration rate (eGFR). The degree of arteriolar hyalinosis was positively correlated with age, night time SBP, s.d. of day time and night time SBP, day time and night time ARV, the N/D ratio of SBP and 7-day SBP, and was negatively correlated with the eGFR. A multiple linear regression analysis revealed that the level of arteriolar hyalinosis, but not arteriosclerosis, was associated with the s.d. of night time SBP (β=0.63, P<0.01) or night time ARV (β=0.61, P<0.01) after adjustment for age, sex, body mass index, the eGFR and night time SBP. Multiple linear regression analyses indicated no significant correlation between the degree of arteriolar hyalinosis and the N/D ratio of SBP or 7-day SBP s.d. or between the degree of arteriosclerosis and any of the BPV parameters. In conclusion, short-term night time BPV was found to be associated with arteriolar hyalinosis in normotensive IgAN patients.

Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

The radiocephalic arteriovenous fistula (AVF) provides optimal vascular access for hemodialysis; it has a higher long-term patency rate and fewer complications than other vascular access methods. However, the AVF has a high primary failure rate. The presence of small-diameter vessels at anastomosis sites is an important risk factor for AVF failure. However, in a recent study, despite selecting an adequate artery and vein for creating an AVF by routine preoperative vascular mapping, AVF maturation and primary failure occurred. Thus, pre-existing arteriosclerosis at AVF anastomosis sites likely contributes to AVF failure. In this review, we discuss the relationship between pathologic changes and AVF patency in hemodialysis patients. Because arteriosclerosis of the major arteries such as the coronary and carotid arteries is associated with cardiovascular mortality, we also review the impact of arteriosclerosis of upper arm arteries at AVF anastomosis sites on cardiovascular mortality in hemodialysis patients.

There is considerable global demand for three-dimensional (3D) functional tissues which mimic our native organs and tissues for use as in vitro drug screening systems and in regenerative medicine. In particular, there has been an increasing number of patients who suffer from arterial diseases such as arteriosclerosis. As such, in vitro 3D arterial wall models that can evaluate the effects of novel medicines and a novel artificial graft for the treatment are required. In our previous study, we reported the rapid construction of 3D tissues by employing a layer-by-layer (LbL) technique and revealed their potential applications in the pharmaceutical fields and tissue engineering. In this study, we successfully constructed a 3D arterial wall model containing vasa vasorum by employing a LbL technique for the first time. The cells were coated with extracellular matrix nanofilms and seeded into a culture insert using a cell accumulation method. This model had a three-layered hierarchical structure: a fibroblast layer, a smooth muscle layer, and an endothelial layer, which resembled the native arterial wall. Our method could introduce vasa vasorum into a fibroblast layer in vitro and the 3D arterial wall model showed barrier function which was evaluated by immunostaining and transendothelial electrical resistance measurement. Furthermore, electron microscopy observations revealed that the vasa vasorum was composed of single-layered endothelial cells, and the endothelial tubes were surrounded by the basal lamina, which are known to promote maturation and stabilization in native blood capillaries. These models should be useful for tissue engineering, regenerative medicine, and pharmaceutical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 814-823, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: To examine whether the long-term resting heart rate (RHR) pattern can predict the risk of having arterial stiffness in a large ongoing cohort., Approach and Results: This community-based cohort included 12 554 participants in the Kailun study, who were free of myocardial infarction, stroke, arrhythmia, and cancer. We used latent mixture modeling to identify RHR trajectories in 2006, 2008, and 2010. We used multivariate linear regression model to examine the association between RHR trajectory patterns and the risk of having arterial stiffness, which was assessed by brachial-ankle pulse wave velocity in 2010 to 2016. We adjusted for possible confounding factors, including socioeconomic status, lifestyle factors, use of medications, comorbidities, and serum concentrations of lipids, glucose, and high-sensitivity C-reactive proteins. We identified 5 distinct RHR trajectory patterns based on their 2006 status and on the pattern of change during 2006 to 2010 (low-stable, moderate-stable, moderate-increasing, elevated-decreasing, and elevated-stable). We found that individuals with elevated-stable RHR trajectory pattern had the highest brachial-ankle pulse wave velocity value and individuals with the low-stable RHR trajectory pattern had the lowest value (adjusted mean difference=157 cm/s; P<0.001). Adjusted odds ratio for risk of having arterial stiffness (brachial-ankle pulse wave velocity ≥1400 cm/s) was 4.14 (95% confidence interval, 2.61-6.57) relative to these 2 extreme categories. Consistently, a higher average RHR, a higher annual RHR increase rate, and a higher RHR variability were all associated with a higher risk of having arterial stiffness., Conclusions: Long-term RHR pattern is a strong predictor of having arterial stiffness., Competing Interests: All authors read and approved the final manuscript. The authors do not have conflicts of interest to disclose., (© 2016 American Heart Association, Inc.)

Retinal vein occlusion (RVO) is a common vascular disease of retina; however, the pathomechanism leading to RVO is not yet clear. In general, increasing age, hypertension, arteriosclerosis, diabetes mellitus, dyslipidemia, cardiovascular disorder, and cerebral stroke are systemic risk factors of RVO. However, RVO often occur in the unilateral eye and sometimes develop in young subjects who have no arteriosclerosis. In addition, RVO show different variations on the degrees of severity; some RVO are resolved without any treatment and others develop vision-threatening complications such as macular edema, combined retinal artery occlusion, vitreous hemorrhage, and glaucoma. Clinical conditions leading to RVO are still open to question. In this review, we discuss how to treat RVO in practice by presenting some RVO cases. We also deliver possible pathomechanisms of RVO through our clinical experience and animal experiments.

Objective The management of blood pressure (BP) in hypertensive patients is the key to preventing a progression of organ damage. The brachial BP (bBP) has been used as the representative method for measuring the BP. The central BP (cBP), which is, different from the bBP due to the propagation and the reflection of the pulse wave in the arterial system, has recently received attention because it can now be estimated non-invasively. We examined the relationships between the difference in the central systolic BP (csBP) and the brachial systolic BP (bsBP) (Δ) and other factors in hypertensive patients. Methods The bsBP and csBP were measured in patients with essential hypertension and the relationships between the bsBP, csBP, or Δ and background factors including age, the brain natriuretic peptide (BNP) level, the estimated glomerular filtration rate (eGFR), flow-mediated vasodilation (an index of vascular endothelial function), the cardio-ankle vascular index (CAVI, an index of arteriosclerosis), and the carotid intima-media thickness (an index of atherosis) were investigated. Results The data of 191 patients were analyzed. Although there was no significant correlation between the CAVI and the bsBP; positive correlations were observed between the CAVI and the csBP (r=0.249, p=0.001). The Δ value showed significant positive correlations with age, and the BNP, eGFR, and CAVI values. Conclusion The csBP is more strongly associated with arteriosclerosis than the bsBP. Moreover, the Δ value is more strongly associated with cardiac function, renal function, and arteriosclerosis than the bsBP or csBP. These data suggested that the Δ value may have a greater prognostic value than the bsBP or csBP and may be worth calculating in the clinical setting.

Aging is a major risk factor for the development of cardiovascular disease. Despite a significant reduction in the mortality and morbidity rates over the last decade, the socio-economic burden of cardiovascular disease is still substantial. Consequently, there is a considerable need for alternative strategies, such as nutraceutical supplementation, that delay the functional vascular decline present in the elderly. Compromised autophagy and oxidative stress (OS) are considered major causes of the age-related endothelial dysfunction. OS reduces the bioavailability of nitric oxide (NO), which has been associated with hypertension, arteriosclerosis, and a reduced vasodilatory response. High levels of free radicals and the low bioavailability of NO lead to a positive feedback loop of further OS, organelle damage, poor repair, and endothelial dysfunction. Here we draw attention to the relationship between OS and autophagy in the aged vasculature. We have reviewed the published literature and provided arguments that support that treatment with resveratrol stimulates autophagy and thereby has the potential to restore oxidative balance in the endothelium, which indicates that treatment with resveratrol might have therapeutic potential to restore endothelial function in the elderly., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Functional and structural changes in the common carotid artery are biomarkers for cardiovascular risk. Current methods for measuring functional changes include pulse wave velocity, compliance, distensibility, strain, stress, stiffness, and elasticity derived from arterial waveforms. The review is focused on the ultrasound-based carotid artery elasticity and stiffness measurements covering the physics of elasticity and linking it to biological evolution of arterial stiffness. The paper also presents evolution of plaque with a focus on the pathophysiologic cascade leading to arterial hardening. Using the concept of strain, and image-based elasticity, the paper then reviews the lumen diameter and carotid intima-media thickness measurements in combined temporal and spatial domains. Finally, the review presents the factors which influence the understanding of atherosclerotic disease formation and cardiovascular risk including arterial stiffness, tissue morphological characteristics, and image-based elasticity measurement.

Background and Aims: Findings of observational studies suggest cardioprotective effects of antioxidant vitamins and carotenoids. However, recent meta-analyses failed to show the beneficial effects of supplemental intake of antioxidants on cardiovascular disease (CVD). We aimed to assess the association between CVD risk and β-cryptoxanthin in Japan, where Satsuma mandarin, a major source of β-cryptoxanthin, is widely consumed., Methods and Results: This was part of the Mikkabi cohort study. Surveys were conducted at baseline, in 2003 and 2005, and on follow-up in 2006, 2009, and 2013. We examined brachial-ankle pulse wave velocity (baPWV) with a high cut-off value set at 18.3 m s(-1). Hazard ratios (HR) and 95% confidence intervals for high baPWV were estimated using a Cox proportional hazards model with adjustment for potential confounders. A total of 635 participants with baPWV of less than 18.3 m s(-1) at baseline were included in the analysis. During the follow-up period of 57,921 person-months, 99 subjects developed high baPWV. After multivariate adjustment, the HR for high baPWV in the highest tertile compared with the lowest tertile was significantly low for β-cryptoxanthin, β-carotene, and total carotenoids. Serum concentrations of β-cryptoxanthin and β-carotene were higher in people who ate Satsuma mandarin frequently. Compared with <1/d intake of Satsuma mandarin, 3-4/d was associated with a low risk of high PWV., Conclusion: This study indicated that β-cryptoxanthin and β-carotene derived from Satsuma mandarin are candidate micronutrients for preventing arteriosclerosis development. Further longitudinal and interventional studies will be required to validate the effect on CVD., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)