Reference values for local arterial stiffness. Part A: carotid artery.

OBJECTIVE: Non-invasive measures of common carotid artery properties, such as diameter and distension, and pulse pressure, have been widely used to determine carotid artery distensibility coefficient - a measure of carotid stiffness (stiffness ∼1/distensibility coefficient). Carotid stiffness has been associated with incident cardiovascular disease (CVD) and may therefore be a useful intermediate marker for CVD. We aimed to establish age and sex-specific reference intervals of carotid stiffness. METHODS: We combined data on 22 708 individuals (age range 15-99 years, 54% men) from 24 research centres worldwide. Individuals without CVD and established cardiovascular risk factors constituted a healthy sub-population (n = 3601, 48% men) and were used to establish sex-specific equations for percentiles of carotid distensibility coefficient across age. RESULTS: In the sub-population without CVD and treatment (n = 12 906, 52% men), carotid distensibility coefficient Z-scores based on these percentile equations were independently and negatively associated, in men and women, respectively, with diabetes {-0.28 [95% confidence interval (CI) -0.41; -0.15] and -0.27 (-0.43; -0.12)}, mean arterial pressure [-0.26 (-0.29; -0.24) and -0.32 (-0.35; -0.29)], total-to-high-density lipoprotein cholesterol ratio [-0.05 (-0.09; -0.02) and -0.05 (-0.11; 0.01)] and BMI [-0.06 (-0.09; -0.04) and -0.05 (-0.08; -0.02)], whereas these were positively associated with smoking [0.30 (0.24; 0.36) and 0.24 (0.18; 0.31)]. CONCLUSIONS: We estimated age and sex-specific percentiles of carotid stiffness in a healthy population and assessed the association between cardiovascular risk factors and carotid distensibility coefficient Z-scores, which enables comparison of carotid stiffness values between (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures.

Reference values for local arterial stiffness. Part B: femoral artery.

OBJECTIVE: Carotid-femoral pulse wave velocity (PWV) is considered the gold standard measure of arterial stiffness, representing mainly aortic stiffness. As compared with the elastic carotid and aorta, the more muscular femoral artery may be differently associated with cardiovascular risk factors (CV-RFs), or, as shown in a recent study, provide additional predictive information beyond carotid-femoral PWV. Still, clinical application is hampered by the absence of reference values. Therefore, our aim was to establish age and sex-specific reference values for femoral stiffness in healthy individuals and to investigate the associations with CV-RFs. METHODS: Femoral artery distensibility coefficient, the inverse of stiffness, was calculated as the ratio of relative diastolic-systolic distension (obtained from ultrasound echo-tracking) and pulse pressure among 5069 individuals (49.5% men, age range: 15-87 years). Individuals without cardiovascular disease (CVD), CV-RFs and medication use (n = 1489; 43% men) constituted a healthy subpopulation used to establish sex-specific equations for percentiles of femoral artery distensibility coefficient across age. RESULTS: In the total population, femoral artery distensibility coefficient Z-scores were independently associated with BMI, mean arterial pressure (MAP) and total to high-density lipoprotein (HDL) cholesterol ratio. Standardized ßs, in men and women, respectively, were -0.18 [95% confidence interval (95% CI) -0.23 to -0.13] and -0.19 (-0.23 to -0.14) for BMI; -0.13 (-0.18 to -0.08) and -0.05 (-0.10 to -0.01) for MAP; and -0.07 (-0.11 to -0.02) and -0.16 (-0.20 to -0.11) for total-to-HDL cholesterol ratio. CONCLUSION: In young and middle-aged men and women, normal femoral artery stiffness does not change substantially with age up to the sixth decade. CV-RFs related to metabolic disease are associated with femoral artery stiffness.

Vascular dysregulation in normal-tension glaucoma is not affected by structure and function of the microcirculation or macrocirculation at rest: a case-control study.

In normal-tension glaucoma (NTG), optic nerve damage occurs despite a normal intraocular pressure. Studies implicating systemic blood pressure or, more recently, arterial stiffness in the pathophysiology of NTG have produced conflicting results. Our aim was to investigate whether NTG is associated with alterations in the macrocirculation or microcirculation, cardiac function, and peripheral and central hemodynamics. Thirty patients with NTG (mean age 65 years, range 46-79) and 33 healthy subjects (mean age 67 years, range 42-79) matched for age and sex were included in the study. Exclusion criteria (for both cases and controls) were history of cardiovascular disease, diabetes mellitus, severe hypertension, and hypercholesterolemia. Aortic stiffness was measured using carotid-femoral pulse wave velocity (PWV), central hemodynamics using carotid artery applanation tonometry, and diameter, stiffness, and intima-media thickness (IMT) of the carotid and femoral artery using echo-tracking. Total peripheral resistance index (TPRI) was derived from mean arterial pressure and cardiac index, measured using ultrasound. There were no statistically significant differences in arterial structure nor function between NTG patients and age and sex-matched controls. NTG versus controls, respectively: brachial blood pressure 126 ± 15/77 ± 8 versus 127 ± 16/76 ± 7 mm Hg, P = 0.81; carotid-femoral PWV 9.8 ± 2.1 versus 10.1 ± 1.9 m/s, P = 0.60; TPRI 1833 ± 609 versus 1779 ± 602 dyne.s/cm5/m2, P = 0.79; and carotid IMT 0.65 ± 0.14 versus 0.68 ± 0.13 mm, P = 0.39. This study could not show an association of NTG with altered IMT, arterial stiffness, total peripheral resistance, cardiac output, and peripheral or central hemodynamics at rest. Although the majority of these NTG patients do exhibit symptoms of vascular dysregulation, in the present study this was not translated into alterations in the microcirculation or macrocirculation at rest.

Asymmetry in prevalence of femoral but not carotid atherosclerosis.

OBJECTIVE(S): Atherosclerotic disease is caused by a combination of systemic and local factors (e.g. geometry) affecting local flow conditions. In contrast to the carotid artery, at the iliac-femoral artery region, a large degree of bilateral asymmetry exists. Therefore, we aimed to determine the influence of body side on the prevalence of atherosclerosis (i.e. plaque and intima-media thickness; IMT) at the carotid and femoral arteries. METHODS: Data were used from the ASKLEPIOS study, including 2524 apparently healthy individuals with a mean age of 46 years (range 35-55 years). Echographic images were obtained bilaterally of the carotid and femoral arteries. A single observer approach was used for the acquisition and quantification of plaques and IMT. RESULTS: The carotid artery displays no significant left-right difference in IMT values nor plaque prevalence (right: 12.0 vs. left 13.3%; P = 0.18). In contrast, for the femoral artery, the IMT distribution at the right common femoral artery is more skewed (P90 right: 1.11 mm, left 1.01 mm; P < 0.001), which is mirrored by a significantly higher plaque prevalence (right: 21.9 vs. left: 15.7%; P < 0.001). CONCLUSION: In the present study, atherosclerotic lesions are more prevalent at the right than at the left femoral artery. This finding highlights the possible role of local arterial geometry in the development of atherosclerosis and underscores the importance of the choice of body side when assessing vascular health.

Cardiovascular risk assessment in low-resource settings: a consensus document of the European Society of Hypertension Working Group on Hypertension and Cardiovascular Risk in Low Resource Settings.

The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 confirms ischemic heart disease and stroke as the leading cause of death and that hypertension is the main associated risk factor worldwide. How best to respond to the rising prevalence of hypertension in resource-deprived settings is a topic of ongoing public-health debate and discussion. In low-income and middle-income countries, socioeconomic inequality and cultural factors play a role both in the development of risk factors and in the access to care. In Europe, cultural barriers and poor communication between health systems and migrants may limit migrants from receiving appropriate prevention, diagnosis, and treatment. To use more efficiently resources available and to make treatment cost-effective at the patient level, cardiovascular risk approach is now recommended. In 2011, The European Society of Hypertension established a Working Group on 'Hypertension and Cardiovascular risk in low resource settings', which brought together cardiologists, diabetologists, nephrologists, clinical trialists, epidemiologists, economists, and other stakeholders to review current strategies for cardiovascular risk assessment in population studies in low-income and middle-income countries, their limitations, possible improvements, and future interests in screening programs. This report summarizes current evidence and presents highlights of unmet needs.

Barriers to antipsychotic discontinuation in nursing homes: an exploratory study.

OBJECTIVES: Despite safety warnings on serious adverse effects and guidance advising discontinuation, antipsychotic use in nursing homes remains high. Studies documenting the barriers experienced to antipsychotic discontinuation are rare. This exploratory study investigates the willingness of nurses and general practitioners (GPs) as well as the barriers to undertake antipsychotic discontinuation. DESIGN AND SETTING: A mixed-method study involving an expert meeting, followed by a survey using structured questionnaires distributed to responsible nurses (primary caregivers) and treating GPs on selected nursing home residents in Belgian nursing homes to generate case-specific information. RESULTS: Antipsychotic users (n = 113) had a mean age of 81 years (range 57-97); 62% were female and 81% had moderate to severe cognitive impairment. Nurses and GPs indicated a willingness for antipsychotic discontinuation in a small proportion of residents, 13.8% and 12.2%, respectively, with a shared willingness in only 4.2%. Residents for whom there was a higher willingness to try antipsychotic discontinuation were generally older (mean age 84.6 vs. 80.3, p = 0.07), had high physical dependency (ADL > 14, 93.3% vs. 60.9%, p = 0.01) and resided on a ward with controlled access (80.0% vs. 45.7%, p = 0.02). In contrast, residents for whom there was a significant lower willingness for discontinuation already had a previously failed discontinuation effort, and may present risk of harm to themselves or to others. Nurses working longer on the ward, with lower education, presented higher barriers to discontinuation of antipsychotics. CONCLUSION: Nurses and GPs share a very low willingness and high barriers to antipsychotic discontinuation. To implement discontinuation programs, complex multidisciplinary interventions should be offered taking existing barriers into account.

Noninvasive assessment of carotid-femoral pulse wave velocity: the influence of body side and body contours.

BACKGROUND: Recently, an expert group advised to measure carotid-femoral (cf) pulse wave velocity (PWV) on the right side of the body, and to use a sliding caliper when tape measure distance cannot be obtained in a straight line. The present study investigates the evidence for this advice by comparing the real travelled cf path lengths (RTPLs) at both body sides and comparing the straight distance (as can be obtained with a sliding caliper) with the tape measure distance. METHODS: RTPLs were measured with MRI in 98 individuals (49 men, age 21-76 years). Path lengths from the aortic arch to the carotid (AA-CA) and femoral (AA-FA) sites were determined. RTPL was calculated as (AA-FA) - (AA-CA) and compared between both sides. RTPLs were compared with 80% of the direct cf distance using a tape measure and the straight cf distance obtained from MRI images. RESULTS: RTPL was slightly longer [11 mm (12), P < 0.001] at the right side. The 80%-rule overestimated RTPLs with 0.5% at the right and 2.7% at the left side. Straight MRI distance tended (P = 0.09) to perform slightly better than tape measure distance. CONCLUSION: The travelled cf path is slightly longer at the right than at the left body side and the straight MRI distance tends to perform better than tape measure distance. The present study supports the advice of the expert consensus group to measure cf-PWV at the right body side using a sliding caliper when tape measure distance cannot be obtained in a straight line.

Ambulatory arterial stiffness index does not accurately assess arterial stiffness.

INTRODUCTION: The ambulatory arterial stiffness index (AASI), derived from ambulatory blood pressure monitoring (ABPM) recordings, has been proposed as a surrogate marker of arterial stiffness. However, there is controversy to what extent it reflects stiffness or is affected by other parameters. Using a previously validated one-dimensional computer model of the arterial circulation, the relative importance of the different determinants of the AASI was explored. METHODS: Arterial distensibility (inverse of stiffness), peripheral resistance, heart rate, maximal cardiac elastance and venous filling pressure were varied from 80 to 120% of their initial value in steps of 10% to generate 3125 BP values, mimicking the daily fluctuations in one theoretical patient. From this dataset, we assessed the confidence with which AASI can be derived in this patient, as well as the influence of different individual parameters on AASI. To assess the ability of AASI to detect large changes in arterial stiffness, two additional patients were simulated with a distensibility of 50 and 25% of the default distensibility, respectively. RESULTS: The distribution of AASI values, obtained from 10 000 ABPM simulations (each using 72 BP values randomly selected among 3125) was normal [AASI = 0.43 ±â€Š0.04 (SD)]. An increase in heart rate, distensibility or resistance from 80 to 120% of its default value caused the AASI to decrease by 37, 21 or 9%, respectively. Whereas there was no overlap in the distensibility ranges for the three theoretical patients, the amount of overlap between the AASI distributions was substantial. CONCLUSION: The confounding effects of vascular resistance and heart rate seriously limit the use of AASI as a marker of stiffness.

Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.

Stiffness of elastic arteries like the aorta predicts cardiovascular risk. By directly reflecting arterial stiffness, having the best predictive value for cardiovascular outcome and the ease of its measurement, carotid-femoral pulse wave velocity is now considered the gold standard for arterial stiffness assessment in daily practice. Many different measurement procedures have been proposed. Therefore, standardization of its measurement is urgently needed, particularly regarding the distance measurement. This consensus document advises on the measurement procedures in general and provides arguments for the use of 80% of the direct carotid-femoral distance as the most accurate distance estimate. It also advises the use of 10 m/s as new cut-off value for carotid-femoral pulse wave velocity.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery.

OBJECTIVES: Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS: In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS: After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg ·â€Šh/L after oral dosing and 52.3 ± 1.3 mg ·â€Šh/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS: This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Systematic appraisal of dementia guidelines for the management of behavioural and psychological symptoms.

BACKGROUND: Within the treatment of dementia, management of behavioural and psychological symptoms (BPSD) is a complex component. PURPOSE: We wanted to offer a pragmatic synthesis of existing specific practice recommendations for managing BPSD, based on agreement among systematically appraised dementia guidelines. DATA SOURCES: We conducted a systematic search in MEDLINE and guideline organisation databases, supplemented by a hand search of web sites. STUDY SELECTION: Fifteen retrieved guidelines were eligible for quality appraisal by the Appraisal of Guidelines Research and Evaluation instrument (AGREE), performed by 2 independent reviewers. DATA EXTRACTION: From the 5 included guidelines, 18 specific practice recommendations for BPSD were extracted and compared for their level of evidence and strength. DATA SYNTHESIS: No agreement was found among dementia guidelines for the majority of specific practice recommendations with regard to non-pharmacological interventions, although these were recommended as first-line treatment. Pharmacological specific practice recommendations were proposed as second-line treatment, with agreement for the use of a selection of antipsychotics based on strong supporting evidence, but with guidance for timely discontinuation. LIMITATIONS: The appraisal of the level of agreement between guidelines for each specific practice recommendation was complicated by variation in grading systems, and was performed with criteria developed a posteriori. CONCLUSION: Despite the limited number of recommendations for which agreement was found, guidelines did agree on careful antipsychotic use for BPSD. Adverse events might outweigh the supporting evidence of efficacy, weakening the recommendation. More pivotal trials on the effectiveness of non-pharmacological interventions, as well as guidelines specifically focusing on BPSD, are needed.

The change in arterial stiffness over the cardiac cycle rather than diastolic stiffness is independently associated with left ventricular mass index in healthy middle-aged individuals.

BACKGROUND: The current standard for arterial stiffness assessment, aortic pulse wave velocity (aPWV), is measured at diastolic pressure. Arterial stiffness, however, is pressure dependent. At the carotid artery level, the degree of this dependency can be quantified as the difference (ΔPWV) between systolic and diastolic (cPWVd) carotid pulse wave velocity. Biomechanically, a greater ΔPWV implies greater increases in left ventricular afterload with physical activity. Therefore, we hypothesized, that ΔPWV is more strongly associated with left ventricular mass index (LVMI) than aPWV and cPWVd. METHODS: In 1776 healthy individuals from the Asklepios cohort (age 35-55 years), ΔPWV was obtained from combined carotid artery ultrasound and tonometry recordings. Multiple linear regression analysis was performed to investigate the associations of ΔPWV, cPWVd and aPWV with LVMI, adjusting for age, sex, mean blood pressure (MBP), central pulse pressure, and other possible confounders. RESULTS: ΔPWV was 2.4 ±â€Š1.2 m/s (mean ±â€ŠSD), ranging from 0.8 m/s, indicating almost constant arterial stiffness over the cardiac cycle, to 4.4 m/s, reflecting substantial pressure dependency. ΔPWV was significantly associated with LVMI (ß of 2.46 g/m per m/s, P < 0.001), even after full adjustment (ß of 0.56 g/m per m/s, P = 0.03). cPWVd and aPWV had clear crude associations with LVMI (P < 0.001), but lost significance after adjustment (ß of -0.48 and -0.33 g/m per m/s, with P = 0.11 and 0.2, respectively). CONCLUSION: The change in arterial stiffness over the cardiac cycle, rather than diastolic stiffness, is independently associated with LVMI in healthy middle-aged individuals. Therefore, the pressure dependency of arterial stiffness should be considered in cardiovascular risk assessment.

Aortic stiffness and central wave reflections predict outcome in renal transplant recipients.

Although renal transplantation improves survival, cardiovascular morbidity and mortality remain significantly elevated compared with nonrenal populations. The negative impact of traditional, uremia-related, and transplantation-related risk factors in this process remains, however, largely unexplored. Surrogate markers such as aortic stiffness and central wave reflections may lead to more accurate cardiovascular risk stratification, but outcome data in renal transplant recipients are scarce. We aimed to establish the prognostic significance of these markers for fatal and nonfatal cardiovascular events in renal transplant recipients. Carotid-femoral pulse wave velocity, central augmentation pressure, and central augmentation index were measured in a cohort of 512 renal transplant recipients using the SphygmoCor system. After a mean follow-up of 5 years, 20 fatal and 75 nonfatal cardiovascular events were recorded. Using receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.718 (95% CI 0.659-0.776) for pulse wave velocity, 0.670 (95% CI 0.604-0.736) for central augmentation pressure, and 0.595 (95% CI 0.529-0.660) for central augmentation index. When we accounted for age, gender, and C-reactive protein in Cox-regression analysis, pulse wave velocity (hazard ratio: 1.349 per 1 SD increase; 95% CI 1.104-1.649; P=0.003) and central augmentation pressure (hazard ratio: 1.487 per 1 SD increase; 95% CI 1.219-1.814; P<0.001) remained independent predictors of outcome. Aortic stiffness and increased wave reflections are independent predictors of cardiovascular events in renal transplant recipients. As single parameter of wave reflection, central augmentation pressure was better than central augmentation index. Combined measurement of pulse wave velocity and central augmentation pressure may contribute to an accurate cardiovascular risk estimation in this heterogeneous population.

Carotid to femoral pulse wave velocity: a comparison of real travelled aortic path lengths determined by MRI and superficial measurements.

OBJECTIVES: Carotid-femoral pulse wave velocity (PWV) is the gold standard method for determination of arterial stiffness. PWV is assessed by dividing travelled distance by travel time. Standardization and validation of the methodology for travelled distance measurement is of crucial importance. The aim of the current investigation was to standardize and validate the methodology for travelled distance measurement. METHODS: Real travelled carotid-femoral path lengths were measured with MRI in 98 healthy men/women (50% men, age 21-76 years) and are used as reference distance. This reference distance was compared with 11 estimates of aortic path length from body surface distances commonly used in PWV measurement, nine of them based on tape measures and two based on body height. Determinants of the difference between reference distance and the best body surface distance were determined. Additionally, the influence of body contours was identified. RESULTS: The tape measure distance from carotid to femoral artery (CA-FA), multiplied by 0.8, yielded the best agreement with the reference aortic path length [difference 0.26 cm (SD 3.8), not statistically significant]. Thirty percent of the variation in difference between the reference distance and tape measure distance (CA-FA × 0.8) was explained by age. Adding BMI increased this number to 34%. CONCLUSION: The tape measure distance from CA-FA, multiplied by 0.8, corresponds best with the real travelled aortic path length. This distance is moderately (yet statistically significantly) influenced by age and minimally by BMI.