Arterial Stiffness: From Basic Primers to Integrative Physiology.

The elastic properties of conductance arteries are one of the most important hemodynamic functions in the body, and data continue to emerge regarding the importance of their dysfunction in vascular aging and a range of cardiovascular diseases. Here, we provide new insight into the integrative physiology of arterial stiffening and its clinical consequence. We also comprehensively review progress made on pathways/molecules that appear today as important basic determinants of arterial stiffness, particularly those mediating the vascular smooth muscle cell (VSMC) contractility, plasticity and stiffness. We focus on membrane and nuclear mechanotransduction, clearance function of the vascular wall, phenotypic switching of VSMCs, immunoinflammatory stimuli and epigenetic mechanisms. Finally, we discuss the most important advances of the latest clinical studies that revisit the classical therapeutic concepts of arterial stiffness and lead to a patient-by-patient strategy according to cardiovascular risk exposure and underlying disease.

Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease.

The cushioning function of large arteries encompasses distension during systole and recoil during diastole which transforms pulsatile flow into a steady flow in the microcirculation. Arterial stiffness, the inverse of distensibility, has been implicated in various etiologies of chronic common and monogenic cardiovascular diseases and is a major cause of morbidity and mortality globally. The first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins that support the mechanical load, while the second important components are vascular smooth muscle cells (VSMCs), which not only regulate actomyosin interactions for contraction but mediate also mechanotransduction in cell-ECM homeostasis. Eventually, VSMC plasticity and signaling in both conductance and resistance arteries are highly relevant to the physiology of normal and early vascular aging. This review summarizes current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis. We further speculate on the contribution of cellular stiffness along the arterial tree to vascular wall stiffness. In addition, this review provides the latest advances in the identification of gene variants affecting arterial stiffening. Now that important hemodynamic and molecular mechanisms of arterial stiffness have been elucidated, and the complex interplay between ECM, cells, and sensors identified, further research should study their potential to halt or to reverse the development of arterial stiffness.

Comparison of Tonotopic and Default Frequency Fitting for Speech Understanding in Noise in New Cochlear Implantees: A Prospective, Randomized, Double-Blind, Cross-Over Study.

OBJECTIVES: While cochlear implants (CIs) have provided benefits for speech recognition in quiet for subjects with severe-to-profound hearing loss, speech recognition in noise remains challenging. A body of evidence suggests that reducing frequency-to-place mismatch may positively affect speech perception. Thus, a fitting method based on a tonotopic map may improve speech perception results in quiet and noise. The aim of our study was to assess the impact of a tonotopic map on speech perception in noise and quiet in new CI users. DESIGN: A prospective, randomized, double-blind, two-period cross-over study in 26 new CI users was performed over a 6-month period. New CI users older than 18 years with bilateral severe-to-profound sensorineural hearing loss or complete hearing loss for less than 5 years were selected in the University Hospital Centre of Rennes in France. An anatomical tonotopic map was created using postoperative flat-panel computed tomography and a reconstruction software based on the Greenwood function. Each participant was randomized to receive a conventional map followed by a tonotopic map or vice versa. Each setting was maintained for 6 weeks, at the end of which participants performed speech perception tasks. The primary outcome measure was speech recognition in noise. Participants were allocated to sequences by block randomization of size two with a ratio 1:1 (CONSORT Guidelines). Participants and those assessing the outcomes were blinded to the intervention. RESULTS: Thirteen participants were randomized to each sequence. Two of the 26 participants recruited (one in each sequence) had to be excluded due to the COVID-19 pandemic. Twenty-four participants were analyzed. Speech recognition in noise was significantly better with the tonotopic fitting at all signal-to-noise ratio (SNR) levels tested [SNR = +9 dB, p = 0.002, mean effect (ME) = 12.1%, 95% confidence interval (95% CI) = 4.9 to 19.2, standardized effect size (SES) = 0.71; SNR = +6 dB, p < 0.001, ME = 16.3%, 95% CI = 9.8 to 22.7, SES = 1.07; SNR = +3 dB, p < 0.001 ME = 13.8%, 95% CI = 6.9 to 20.6, SES = 0.84; SNR = 0 dB, p = 0.003, ME = 10.8%, 95% CI = 4.1 to 17.6, SES = 0.68]. Neither period nor interaction effects were observed for any signal level. Speech recognition in quiet ( p = 0.66) and tonal audiometry ( p = 0.203) did not significantly differ between the two settings. 92% of the participants kept the tonotopy-based map after the study period. No correlation was found between speech-in-noise perception and age, duration of hearing deprivation, angular insertion depth, or position or width of the frequency filters allocated to the electrodes. CONCLUSION: For new CI users, tonotopic fitting appears to be more efficient than the default frequency fitting because it allows for better speech recognition in noise without compromising understanding in quiet.

Mechanisms of Arterial Stiffening: From Mechanotransduction to Epigenetics.

Arterial stiffness is a major independent risk factor for cardiovascular complications causing isolated systolic hypertension and increased pulse pressure in the microvasculature of target organs. Stiffening of the arterial wall is determined by common mechanisms including reduced elastin/collagen ratio, production of elastin cross-linking, reactive oxygen species-induced inflammation, calcification, vascular smooth muscle cell stiffness, and endothelial dysfunction. This brief review will discuss current biological mechanisms by which other cardiovascular risk factors (eg, aging, hypertension, diabetes mellitus, and chronic kidney disease) cause arterial stiffness, with a particular focus on recent advances regarding nuclear mechanotransduction, mitochondrial oxidative stress, metabolism and dyslipidemia, genome mutations, and epigenetics. Targeting these different molecular pathways at different time of cardiovascular risk factor exposure may be a novel approach for discovering drugs to reduce arterial stiffening without affecting artery strength and normal remodeling.

Type 2 Diabetes Mellitus Is Independently Associated With Decreased Neural Baroreflex Sensitivity: The Paris Prospective Study III.

OBJECTIVE: Impaired baroreflex function is an early indicator of cardiovascular autonomic imbalance. Patients with type 2 diabetes mellitus (T2D) have decreased baroreflex sensitivity (BRS), however, whether the neural BRS (nBRS) and mechanical component of the BRS is altered in those with high metabolic risk (HMR, impaired fasting glucose and metabolic syndrome) or with overt T2D, is unknown. We examined this in a community-based observational study, the Paris Prospective Study III (PPS3). Approach and Results: In 7626 adults aged 50 to 75 years, resting nBRS (estimated by low-frequency gain, from carotid distension rate and RR [time elapsed between two successive R waves] intervals) and mechanical BRS were measured by high-precision carotid echotracking. The associations between overt T2D or HMR as compared with subjects with normal glucose metabolism and nBRS or mechanical BRS were quantified using multivariable linear regression analysis. There were 319 subjects with T2D (61±6 years, 77% male), 1450 subjects with HMR (60±6 years, 72% male), and 5857 subjects with normal glucose metabolism (59±6 years, 57% male). Compared with normal glucose metabolism, nBRS was significantly lower in HMR subjects (ß=-0.07 [95% CI, -0.12 to -0.01]; P=0.029) and in subjects with T2D (ß=-0.18 [95% CI, -0.29 to -0.07]; P=0.002) after adjustment for confounding and mediating factors. Subgroup analysis suggests significant and independent alteration in mechanical BRS only among HMR patients who had both impaired fasting glucose and metabolic syndrome. CONCLUSIONS: In this community-based study of individuals aged 50 to 75, a graded decrease in nBRS was observed in HMR subjects and patients with overt T2D as compared with normal glucose metabolism subjects.

EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model.

The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.

Aortic stiffness is not only associated with structural but also functional parameters of retinal microcirculation.

OBJECTIVE: The aim of the study was to test the hypothesis that alterations in large arteries are associated with microvascular remodelling and decreased retinal capillary blood flow. METHODS: The study group comprised of 88 patients with essential hypertension and 32 healthy controls. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of arterial stiffness measurement (carotid-femoral pulse wave velocity), its hemodynamic consequences (central pulse pressure, augmentation pressure, augmentation index) and intima media thickness of common carotid artery. RESULTS: Pulse wave velocity was inversely correlated to mean retinal capillary blood flow in hypertensive patients (R = -0.32, p < 0.01). This relationship remained significant in multivariate regression analysis after adjustment for age, sex, central systolic blood pressure (BP) and body mass index (ß = -31.27, p < 0.001). Lumen diameter (LD) of retinal arterioles was significantly smaller in hypertensive then normotensive subjects (79.4 vs. 83.8, p = 0.03). Central and brachial systolic, diastolic and mean BPs were significantly correlated with LD and outer diameter of retinal arterioles. The relationship between LD and central BPs remained significant in multivariate analysis (ß = -0.15, p = 0.03 for cSBP; ß = -0.22, p = 0.04 for cDBP; ß = -0.21, p = 0.03 for cMBP). Moreover, in a subgroup with cardiac damage central and brachial pulse pressure were positively associated with retinal wall thickness, wall cross sectional area, and wall to lumen ratio. CONCLUSION: In conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.

Ecological Studies of Sleep Disturbances During Suicidal Crises.

PURPOSE OF REVIEW: Several reviews and metanalyses have shown that sleep disturbances, such as insomnia and nightmares, can predict suicidal ideations and behaviors. Common physio-pathological pathways may explain this relationship. However, only in recent years, some research groups have tried to apply this knowledge in the quest for a reliable tool of suicide risk prediction. We aim to describe in this paper the results of studies using ecological or quasi-ecological assessment methods that connect sleep disturbances and suicide risk. RECENT FINDINGS: Our review confirms the paucity of studies on this topic. The few studies that we could analyze suggest the interest of ecological methods of sleep assessment since sleep disturbances predicted the onset or worsening of suicidal ideations and behaviors. Ecological assessment of sleep can help to understand how sleep disturbances contribute to the emergence of suicidal ideations and behaviors. Sleep disturbances appear as a promising "real-life" marker of risk, but further studies are needed to determine if sleep monitoring could guide preventive interventions.

[Lancet Commission on Hypertension Group position statement on the global improvement of accuracy standards for devices that measure blood pressurePosicionamento do Grupo da Lancet Commission on Hypertension sobre a melhoria global dos padrões de acurácia para aparelhos que medem a pressão arterial]. / Declaración de posición del Grupo de la Comisión Lancet de Hipertensión con respecto a la mejora mundial de las normas de exactitud para los dispositivos de medición de la presión arterial.

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.

A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas on-line de aparelhos com acurácia adequada que sejam acessíveis aos consumidores e profissionais de saúde. As recomendações estão alinhadas com as políticas da Organização Mundial da Saúde (OMS) sobre dispositivos médicos e atenção universal à saúde. A adesão às recomendações aumentaria a oferta global de dispositivos de pressão arterial com acurácia adequada e resultaria em melhor diagnóstico e tratamento da hipertensão arterial, diminuindo assim a carga mundial dessa doença.

Impaired baroreflex sensitivity, carotid stiffness, and exaggerated exercise blood pressure: a community-based analysis from the Paris Prospective Study III.

Aims: People with exaggerated exercise blood pressure (BP) have adverse cardiovascular outcomes. Mechanisms are unknown but could be explained through impaired neural baroreflex sensitivity (BRS) and/or large artery stiffness. This study aimed to determine the associations of carotid BRS and carotid stiffness with exaggerated exercise BP. Methods and results: Blood pressure was recorded at rest and following an exercise step-test among 8976 adults aged 50 to 75 years from the Paris Prospective Study III. Resting carotid BRS (low frequency gain, from carotid distension rate, and heart rate) and stiffness were measured by high-precision echotracking. A systolic BP threshold of ≥ 150 mmHg defined exaggerated exercise BP and ≥140/90 mmHg defined resting hypertension (±antihypertensive treatment). Participants with exaggerated exercise BP had significantly lower BRS [median (Q1; Q3) 0.10 (0.06; 0.16) vs. 0.12 (0.08; 0.19) (ms2/mm) 2×108; P < 0.001] but higher stiffness [mean ± standard deviation (SD); 7.34 ± 1.37 vs. 6.76 ± 1.25 m/s; P < 0.001) compared to those with non-exaggerated exercise BP. However, only lower BRS (per 1SD decrement) was associated with exaggerated exercise BP among people without hypertension at rest {specifically among those with optimal BP; odds ratio (OR) 1.16 [95% confidence intervals (95% CI) 1.01; 1.33], P = 0.04 and high-normal BP; OR, 1.19 (95% CI 1.07; 1.32), P = 0.001} after adjustment for age, sex, body mass index, smoking, alcohol, total cholesterol, high-density lipoprotein cholesterol, resting heart rate, and antihypertensive medications. Conclusion: Impaired BRS, but not carotid stiffness, is independently associated with exaggerated exercise BP even among those with well controlled resting BP. This indicates a potential pathway from depressed neural baroreflex function to abnormal exercise BP and clinical outcomes.

Non-invasive hemodynamic monitoring as a guide to drug treatment of uncontrolled hypertensive patients: effects on home blood pressure in the BEAUTY study.

BACKGROUND: In the BEAUTY study we investigated whether utilizing non-invasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management-IHM) compared to conventional drug selection may improve home BP in patients with uncontrolled hypertension. METHODS: Uncontrolled (office systolic blood pressure (SBP) > 140 mmHg and ambulatory daytime SBP >135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to 5 European Hypertension Excellence Centers and, if eligible, were randomized into IHM-guided vs conventional treatment adjustment. Home blood pressure (BP) was taken with 2 repeated readings at 1-2 min intervals in the morning and in the evening (before drug intake and eating) during the week preceding the visit at the outpatient clinic after 5 min rest using a validated semi-automatic oscillometric arm cuff device and with a correct cuff bladder placement. Home blood pressure was measured in a sub-group of patients (n = 84) not significantly different from the other patients. RESULTS: Home SBP changed from 152.1+/-15.8 and 149.8+/-11.8 mmHg to 131.0 +/-11.1 and 139.6+/-12.8 mmHg in IHM group (n = 46) and Control group (n = 38), respectively, showing significantly greater reduction in IHM than in Control group (d= -10.9 mmHg, 95% CI -17.77, -4.02), p = 0.002. The reduction remained significant after multiple adjustments, particularly for baseline home SBP, recruiting center, age, sex and BMI (SBPIHM-Control= -9,63 mmHg, 95% CI -14.28, -5.11) mmHg, p < 0.0001). CONCLUSION: Drug selection algorithm based on non-invasive hemodynamic monitoring induced larger reduction in home BP compared to conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence Centers. Although the main BEAUTY study was negative, these home BP measurements taken by patients themselves may suggest that the integrated hemodynamic monitoring is useful in patients with uncontrolled hypertension. This finding might depend on specific features of home BP measurements which could make it recommended BP measurement method for drug trials.

2018 Practice Guidelines for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.

New estimate of valvuloarterial impedance in aortic valve stenosis: A cardiac magnetic resonance study.

PURPOSE: Valvuloarterial impedance (ZVA ), estimating left ventricle (LV) afterload, has been proposed in transthoracic echocardiography (TTE) as a predictor of mortality in aortic valve stenosis (AVS). However, its calculation differs from arterial characteristic impedance (ZC ). Our aim was to apply the concept of ZC calculation to estimate ZVA from MR with carotid tonometry and to evaluate these indices through their associations with symptoms, LV diastolic function and aortic stiffness. MATERIALS AND METHODS: In 40 patients with AVS (76 ± 13 years), ZVA-TI derived from velocity time integral and E/Ea were estimated by TTE. ZVA-INS , based on ZC formula, calculated as the instantaneous pressure gradient to peak flow ratio and aortic compliance were estimated by using MRI at 1.5 Tesla. RESULTS: Both ZVA estimates were higher in symptomatic than asymptomatic patients (707 ± 22 versus 579 ± 53 dyne.s/cm5 , P = 0.031 for ZVA-INS and 4.35 ± 0.16 versus 3.33 ± 0.38 mmHg.m2 /mL, P = 0.018 for ZVA-TI ). Although they were both associated with aortic compliance (r = -0.45; P = 0.006 for ZVA-INS and r = -0.43; P = 0.008 for ZVA-TI ) only ZVA-INS was associated with E/Ea (r = 0.50; P < 0.001). In multivariate analysis to identify determinants of E/Ea, a model including age, mean blood pressure, LV ejection fraction, LV mass, and aortic valve area was performed (R2 = 0.41; P < 0.01). When ZVA-INS was added to the model, its overall significance was higher R2 = 0.56 (P < 0.01) and ZVA-INS and LV mass were the only significant determinants. CONCLUSION: ZVA-INS was more strongly associated with diastolic dysfunction than usual parameters quantifying AVS severity. This new ZVA estimate could improve LV afterload evaluation. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:795-803.

The structural factor of hypertension: large and small artery alterations.

Pathophysiological studies have extensively investigated the structural factor in hypertension, including large and small artery remodeling and functional changes. Here, we review the recent literature on the alterations in small and large arteries in hypertension. We discuss the possible mechanisms underlying these abnormalities and we explain how they accompany and often precede hypertension. Finally, we propose an integrated pathophysiological approach to better understand how the cross-talk between large and small artery changes interacts in pressure wave transmission, exaggerates cardiac, brain and kidney damage, and lead to cardiovascular and renal complications. We focus on patients with essential hypertension because this is the most prevalent form of hypertension, and describe other forms of hypertension only for contrasting their characteristics with those of uncomplicated essential hypertension.

Antihypertensive drugs.

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators.

Arterial (Aortic) Stiffness in Patients with Resistant Hypertension: from Assessment to Treatment.

PURPOSE OF REVIEW: The purpose of the review is to examine whether measurement of aortic stiffness could be especially value-adding for risk stratification and treatment among patients with resistant hypertension (RH). RECENT FINDINGS: Adverse arterial remodeling and increased aortic stiffness is associated with RH, and it may be of additional clinical benefit to measure aortic stiffness in these patients. However, there is insufficient evidence to determine whether aortic stiffness is excessively high relative to the level of blood pressure (BP) among people with RH. This issue needs resolution as it could help refine management decisions guided by aortic stiffness. If conventional antihypertensive therapy fails to lower BP in patients with RH, there is good rationale for effectiveness of spironolactone as add on therapy, and this should also improve aortic stiffness. Lifestyle intervention with exercise and diet should be additionally efficacious towards improving BP and aortic stiffness in patients with RH, but there is limited data in this patient population. For better characterization on the effects of BP treatment on aortic stiffness, measures of central aortic BP may help refine management decisions above and beyond conventional arm cuff BP. There is strong evidence to support the use of aortic stiffness as a tool to aid risk stratification in hypertension management. Although there is a theoretical basis for special additional benefit of measuring aortic stiffness in patients with RH (as distinct from uncomplicated hypertension), at this time, there is inadequate data available to make definitive conclusions and is an area for future investigation.

Ideal Cardiovascular Health and Subclinical Markers of Carotid Structure and Function: The Paris Prospective Study III.

OBJECTIVE: We hypothesized that subclinical markers of vascular structure and function, which are independent predictors of cardiovascular disease, would be less frequent in subjects with ideal than poor cardiovascular health (CVH) as defined by the American Heart Association (AHA). APPROACH AND RESULTS: Carotid parameters were measured using high-precision echotracking device in 9155 nonreferred participants attending a health checkup in a large health center in Paris (France) between 2008 and 2012. According to the AHA, participants with 0 to 2, 3 to 4, and 5 to 7 metrics (smoking, physical activity, body mass index, diet, blood glucose and total cholesterol, blood pressure) at the ideal level were categorized as having poor, intermediate, and ideal CVH. Carotid parameters were dichotomized according to their median value, and multivariable logistic regression analysis was performed. Mean age was 59.5 (SD 6.3) years; 39% were females, and ideal CVH was present in 10.11% of the study participants. After adjustment for age, sex, education, and living alone and compared with a poor CVH, an ideal CVH was associated with lower common carotid artery intima-media thickness (odds ratio=1.64; 95% confidence interval 1.40, 1.93), absence of carotid plaques (odds ratio=2.14; 95% confidence interval 1.60, 2.87), lower Young's elastic modulus (odds ratio=2.43; 95% confidence interval 2.07, 2.84), and higher carotid distensibility coefficient (odds ratio=2.90; 95% confidence interval 2.47, 3.41). CONCLUSIONS: In community subjects aged 50 to 75 years, ideal CVH was associated with substantially less arterial stiffness and thickness. These associations might contribute to the lower risk of cardiovascular diseases in subjects with ideal CVH.

Oxysterols direct immune cell migration via EBI2.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3ß,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.

Sedentary Behavior and Arterial Stiffness in Adults with and without Metabolic Syndrome.

This study aimed to investigate whether sedentary time (Sed) and physical activity (PA) are associated with arterial stiffness in individuals with and without metabolic syndrome (MetS). This cross-sectional study comprised 197 individuals (47±13 years; 58% female) from a primary health care centre. Arterial stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV). Metabolic syndrome was determined as clustering of at least 3 out of 5 risk factors (central obesity, hypertension, impaired glucose, triglycerides and high-density lipoprotein cholesterol). Daily PA was objectively assessed and classified in Sed, light and moderate-to-vigorous PA. Physical activity was used as a continuous variable for multiple regression analysis. For mean comparisons of cfPWV between subjects with and without MetS, a binary split at the median of Sed and PA was used. Sedentary time was associated with cfPWV (ß=0.11; p=0.01) explaining 1.3% of its variance; independently of age (ß=0.49; p<0.001), systolic blood pressure (ß=0.27; p<0.001) and fasting glucose (ß=0.19; p<0.001). Participants with MetS and more Sed had higher cfPWV than those with MetS and less Sed (9.9±1.0 vs. 8.9±1.0 m/s; p<0.05). Sedentary time is associated with cfPWV independently of age and metabolic risk factors. A higher Sed in MetS individuals lead to a worse arterial stiffness profile.