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.

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.

The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels.

PURPOSE: Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs, but are associated with cardiovascular side-effects. Atosiban, a newer drug, is a competitive antagonist of oxytocin and has been claimed to have fewer cardiovascular side effects. Until now, there has mainly been a subjective reporting of adverse reactions and few objective cardiovascular data. Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban compared with placebo on cardiac function, large artery properties, blood pressure, and resistance vessels. METHODS: A double-blind, randomized trial was carried out in 20 non-pregnant female volunteers. Hemodynamic measurements were made under standardized conditions during kinetic steady state. Cardiac output was measured with echocardiography, large artery properties with an echo-tracking device. The effect on the microcirculation was estimated using the total peripheral resistance index (TPRI). RESULTS: Atosiban did not differ from placebo. With ritodrine, cardiac function increased by 79% compared with placebo because of a rise in heart rate (91%). TPRI decreased by 48%. Ritodrine increased the distensibility of the common carotid artery by 62% and the compliance by 83%, independent of blood pressure. Compliance of the common femoral artery increased independently of pressure by 33% and the distensibility by 59%. Aortic pulse wave velocity was not influenced by either medication. CONCLUSIONS: The present study shows potential beneficial vascular effects of ritodrine that are counterbalanced by the cardiac effects. Atosiban has no clinically relevant cardiovascular effects and may be a good alternative for ritodrine in pregnant women at risk of cardiovascular complications.

Prices of antihypertensive medicines in sub-Saharan Africa and alignment to WHO's model list of essential medicines.

OBJECTIVE: To investigate compliance of National Essential Medicines Lists (NEMLs) with the WHO Essential Medicines List (WHO/EML) in 2007 and to compare prices of antihypertensive drugs in and between 13 sub-Saharan African countries. METHODOLOGY: Data on NEMLs and drug prices were collected from 65 public and 65 private pharmacies (five of each per country). Prices were compared with the International Drug Price Indicator Guide (IDPIG). The cost of drug treatment within a country was calculated using defined daily doses (DDD) and between countries using DDD prices adjusted for purchasing power parity-based gross domestic product per capita. RESULTS: All surveyed countries had a NEML. However, none of these lists were in complete alignment with the 2007 WHO/EML, and 38% had not been updated in the last 5 years. Surveyed medicines were cheaper when on the NEMLs; they were also cheaper in public than in private pharmacies. Prices varied greatly per medicine. A large majority of the public prices were higher than those indicated by the IDPIG. Overall, hydrochlorothiazide is the cheapest drug. CONCLUSION: There are substantial differences in NEML composition between the 13 countries. The proportion of NEMLs not regularly updated was double the global United Nations estimates. Prices of WHO/EML-advised drugs differ greatly between drugs and for each drug within and between countries. In general, the use of drugs on the NEML improves financial accessibility, and these drugs should be prescribed preferentially.

Bias in benefit-risk appraisal in older products: the case of buflomedil for intermittent claudication.

Benefit-risk assessment should be ongoing during the life cycle of a pharmaceutical agent. New products are subjected to rigorous registration laws and rules, which attempt to assure the availability and validity of evidence. For older products, bias in benefit-risk assessment is more likely, as a number of safeguards were not in place at the time these products were registered. This issue of bias in benefit-risk assessment of older products is illustrated here with an example: buflomedil in intermittent claudication. Data on efficacy were retrieved from a Cochrane systematic review. Data on safety were obtained by comparing the number of reports of serious adverse events and fatalities published in the literature with those reported in postmarketing surveillance databases. In the case of efficacy, the slim basis of evidence for the benefit of buflomedil is undermined by documented publication bias. In the case of safety, bias in reporting to international safety databases is illustrated by the discrepancy between the number of drug-related deaths published in the literature (20), the potentially drug-related deaths in the WHO database (20) and deaths attributed to buflomedil in the database of the international marketing authorization holder (11). In older products, efficacy cannot be evaluated without a thorough search for publication bias. For safety, case reporting of drug-related serious events and deaths in the literature remains a necessary instrument for risk appraisal of older medicines, despite the existence of postmarketing safety databases. The enforcement of efficient communication between healthcare workers, drug companies, national centres of pharmacovigilance, national poison centers and the WHO is necessary to ensure the validity of postmarketing surveillance reporting systems. Drugs considered obsolete because of unfavourable benefit-risk assessment should not be allowed to stay on the market.

Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population.

BACKGROUND: The relationship between aortic (carotid-femoral) pulse wave velocity and stiffness measures based on local diameter and pressure readings is not yet fully understood. METHODS: We compared the relationship with age and gender of aortic pulse wave velocity to stiffness indices (compliance and distensibility coefficient) evaluated at the common carotid and femoral arteries in 2195 (1131 women) apparently healthy subjects, aged 35-55 years participating in the Asklepios study. Aortic pulse wave velocity was further compared with previously reported central arterial stiffness parameters on the same population. Subjects were divided into four age groups for analysis. RESULTS: Femoral arterial stiffness was higher in men than in women (P < 0.001) but did not change with age and no age-gender interaction was evident. Carotid arterial stiffness increased with age (P < 0.001) and showed a significant (P < 0.001) age-gender interaction, with carotid stiffness increasing more rapidly in women than in men, crossing over around the age of 45. Aortic pulse wave velocity did not differ between men and women, but did increase with age (P < 0.001). No age-gender interaction was evident. CONCLUSION: The relation with age and gender of local and central stiffness measures is not the same over the age range 35-55 in apparently healthy men and women. Depending on the central stiffness parameter used, age-gender effects evident at the carotid artery are or are not found centrally. Though the relevance of these differences requires further evaluation in a longitudinal study with outcome data, they need to be kept in mind when designing or interpreting results from arterial stiffness evaluation studies.

Efficacy and tolerability of nebivolol compared with other antihypertensive drugs: a meta-analysis.

BACKGROUND AND OBJECTIVE: Lowering BP to normal levels without quality of life deterioration is the most important means of reducing cardiovascular risk. Recent studies have challenged the position of beta-adrenoceptor antagonists (beta-blockers) as first-line antihypertensive drugs. Nebivolol is a third-generation, highly selective beta(1)-blocker that causes vasodilation through nitric oxide (NO) release. This meta-analysis investigates the efficacy and tolerability of nebivolol compared with other antihypertensive drugs and placebo in patients with hypertension. METHODS: Twelve randomized controlled studies were included in which nebivolol 5 mg once daily was compared with the recommended clinical doses of other antihypertensive drugs (n = 9), placebo (n = 2), and both (n = 1). The clinical studies were selected after a MEDLINE search up to 2007 using the key words 'nebivolol' and 'hypertension.' RESULTS: Antihypertensive response rates (the percentage of patients achieving target BP levels or a defined DBP reduction) were higher with nebivolol than with ACE inhibitors (odds ratio [OR] 1.92; p = 0.001) and all antihypertensive drugs combined (OR 1.41; p = 0.001) and similar to beta-blockers, calcium channel antagonists (CCAs) and the angiotensin receptor antagonist (ARA) losartan. Moreover, a higher percentage of patients receiving nebivolol achieved target BP levels compared with patients treated with losartan (OR 1.98; p = 0.004), CCAs (OR 1.44; p = 0.024), and all antihypertensive drugs combined (OR 1.35; p = 0.012). The percentage of patients experiencing adverse events did not differ between nebivolol and placebo; adverse event rates were significantly lower with nebivolol than losartan (OR 0.52; p = 0.016), other beta-blockers (OR 0.56; p = 0.007), nifedipine (OR 0.49; p < 0.001), and all antihypertensive drugs combined (OR 0.59; p < 0.001). CONCLUSION: Results of previous pharmacokinetic studies suggest that nebivolol 5 mg may not conform completely to the definition of a classic beta-blocker demonstrating additional antihypertensive effect due to endothelial NO release-mediated vasodilation. This meta-analysis showed that nebivolol 5 mg achieved similar or better rates of treatment response and BP normalization than other drug classes and other antihypertensive drugs combined, with similar tolerability to placebo and significantly better tolerability than losartan, CCAs, other beta-blockers, and all antihypertensive drugs combined. Although not definitive, this meta-analysis suggests that nebivolol 5 mg is likely to have advantages over existing antihypertensives and may have a role in the first-line treatment of hypertension.

Acute central hemodynamic effects of a volume exchange in peritoneal dialysis.

BACKGROUND: Although peritoneal dialysis is considered to offer more hemodynamic stability than hemodialysis, the acute hemodynamic effects of peritoneal dialysis have only been investigated scarcely. The present study assesses the central hemodynamic impact of volume infusion using pH-adjusted icodextrin, thus avoiding interference of glucose, pH, and osmolarity. METHODS: Patients were randomized to 3 different starting volumes (A: 1000 mL, B: 1500 mL, and C: 2500 mL) of icodextrin, followed by addition (A and B) or drainage (C) of 200 mL every 10 minutes for 50 minutes. Local carotid systolic blood pressure (BP; as a surrogate for central BP), augmentation index, and augmentation pressure were measured by applanation tonometry before and after infusion of the starting volumes and after each volume change. RESULTS: We included 13 patients (median age 57 years). Baseline brachial BP was 126/77 mmHg. After infusion of the starting volume, carotid systolic BP and augmentation pressure increased by 4.7 mmHg (p = 0.006) and 3.1 mmHg (p = 0.015). Augmentation index increased by 5.7% (p = 0.04) and heart rate decreased by 2.6/minute (p = 0.006). Intraperitoneal pressure increased by 2.3 cm H(2)O (p = 0.03). No additional hemodynamic changes except for a rise in diastolic BP with increasing volume (p = 0.004) were observed after subsequent addition or removal of volumes. CONCLUSIONS: Infusion of peritoneal dialysis fluids causes an acute increase in carotid systolic BP, followed by a progressive rise in diastolic BP. These effects persist until complete drainage of the abdomen and may be due to an enhanced preload, resulting from intraperitoneal venous compression, and/or increased wave reflection.

Assessment of pressure wave reflection: getting the timing right!

Assessment of timing and magnitude of wave reflection is ideally based on wave separation analysis (WSA). In clinical practice, however, waveform analysis (WFA) is often used to study wave reflection, with different coexisting approaches to assess 'landmarks' on the waveform which are indicative for return of the reflected wave. The aim of this work was to compare WSA and WFA. Data were obtained from 2132 subjects (1093 women) aged between 35 and 56 and free from overt cardiovascular disease. Carotid pressure and aortic flow waveforms, and carotid-femoral pulse wave velocity were measured non-invasively. WSA yielded the timing of return of reflected wave (T(f-b)), the ratio of forward and backward pressure wave (P(b)/P(f)), and the effective length of the arterial tree (L(eff)). WFA resulted in identification of the shoulder (T(sho)) or inflection point (T(inf)) as landmark points, with subsequently derived augmentation index and L(eff) (AIx(sho) and L(eff,sho), AIx(inf) and L(eff,inf), respectively). (i) Neither T(inf) nor T(sho) corresponded with the timing obtained from WSA. (ii) Measurements of L(eff) were found to decrease with age (conforming with current physiological insights) whilst L(eff,inf) was found to increase with age in women, and mixed results were obtained for L(eff,sho). (iii) Both AIx(inf) and AIx(sho) showed a persistent gender difference which was not present in P(b)/P(f). Using the pressure at T(f-b) to calculate AIx, the systematic gender difference in AIx(f-b) was greatly reduced. Analysis of pressure wave reflection is optimally based on measurement of pressure and flow, rather than on waveform analysis alone.

Is the Migraid device an asset in the non-pharmacologic treatment of migraine?

Non-pharmacologic treatment of migraine attacks is advised by guidelines to be considered. Some patients use digital massage of the temporal arteries. The Migraid device exerts a constant pressure on the temporal arteries and may be an alternative for the tiring digital massage. The present study investigates whether the new Migraid device may improve migraine symptoms. In a randomised multi-centre cross-over study the efficacy, safety and tolerability of a 1-hour use of the Migraid device at the start of the aura is compared with no-device in the treatment of migraine attacks with typical aura. Of the 134 patients who entered the study, 98 were suitable for the intention-to-treat analysis and 83 patients completed the study. Data on 94 Migraid treated and 87 non-treated attacks have been analysed. Twelve percent of patients (10/83) were pain-free at 2 hours in the Migraid group versus 1.6% (1/64) in the non-treated group (p = 0.02). After 24-hours 9.6% of patients were pain-free with the Migraid versus 0% with no treatment. After 2 hours 31.3% of patients perceived the migraine headache as severe using the Migraid versus 53.1% with no treatment. For nausea this was 6.1% and 15.6%, respectively (p = 0.01). The device was well tolerated. In conclusion, 1-hour use of the Migraid device at the start of the aura improved headache and other migraine symptoms compared to no treatment. Future research with a more appropriate control should determine whether the Migraid effects are going beyond unspecific placebo effects.

Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Hypertension promotes carotid intima-media thickening. We reviewed the randomized controlled trials that evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intima-media thickness. METHODS: We searched the PubMed and the Web of Science databases for randomized clinical trials, published in English before 2005, and included 22 trials. RESULTS: In 8 trials including 3329 patients with diabetes or coronary heart disease, antihypertensive treatment initiated with an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, or a calcium-channel blocker (CCB), compared with placebo or no-treatment, reduced the rate of intima-media thickening by 7 microm/year (P=0.01). In 9 trials including 4564 hypertensive patients, CCBs, ACE inhibitors, an angiotensin II receptor blocker or an alpha-blocker, compared with diuretics or beta-blockers, in the presence of similar blood pressure reductions, decreased intima-media thickening by 3 microm/year (P=0.03). The overall beneficial effect of the newer over older drugs was largely attributable to the decrease of intima-media thickening by 5 microm/year (P=0.007) in 4 trials of CCBs involving 3619 patients. In 5 trials including 287 patients with hypertension or diabetes, CCBs compared with ACE inhibitors did not differentially affect blood pressure, but attenuated intima-media thickening by 23 microm/year (P=0.02). The treatment induced changes in carotid intima-media thickness correlated with the changes in lumen diameter (P=0.02), but not with the differences in achieved blood pressure (P>0.53). CONCLUSIONS: CCBs reduce carotid intima-media thickening. This mechanism might contribute to their superior protection against stroke.

Reference values for SphygmoCor measurements in South Africans of African ancestry.

BACKGROUND: Measurements of blood pressure (BP) together with applanation tonometry at the radial and femoral arteries allow for reproducible assessments of various indexes of arterial stiffness, including peripheral (PP(p)) and central (PP(c)) pulse pressures, peripheral (AI(p)) and central (AI(c)) augmentation indexes, and aortic pulse wave velocity (PWV). In the absence of an outcome-driven and ethnicity-specific reference frame, we defined preliminary diagnostic thresholds for subjects of African descent living in Africa, using the distributional characteristics of these hemodynamic measurements. METHODS: We randomly recruited 347 subjects from a South African population of African origins. The PP(p) was the average difference between systolic and diastolic BP measured five times consecutively at one home visit. For measurement of PP(c), AI(p), AI(c), and PWV, we used a high-fidelity micromanometer interfaced with a laptop computer running the SphygmoCor software. For analyses we selected 185 subjects without hypertension, diabetes, and previous or concomitant cardiovascular disease. RESULTS: Mean age (33.5 years) was similar in 77 men and 108 women. The PP(p), PP(c), AI(p), AI(c), and PWV significantly increased with age. The 95th prediction bands of this relation at age 30 years, approximated to 70 mm Hg for PP(p), 50 mm Hg for PP(c), 100% for AI(p), 40% for AI(c), and 8.0 m/sec for PWV. The aforementioned thresholds would need adjustment by approximately 2.5 mm Hg, 4.0 mm Hg, 10%, 6%, and 1.0 m/sec, respectively, for each decade that age differs from 30 years. CONCLUSIONS: Pending validation in prospective outcome-based studies 70 mm Hg for PP(p), 50 mm Hg for PP(c), 100% for AI(p), 40% for AI(c), and 8.0 m/sec might be considered as preliminary thresholds to diagnose increased arterial stiffness in young adult subjects of African descent.

Obesity is associated with increased arterial stiffness from adolescence until old age.

OBJECTIVE: To our knowledge, only two previous studies have investigated the age dependence of the relationship between the characteristics of large arteries and excessive body weight. We therefore investigated whether the relationship between arterial stiffness and body mass index (BMI) was consistent across an age range from 10 to 86 years. METHODS: Using a cross-sectional population-based design, we randomly recruited 1306 individuals (median age 43.9 years; 50.5% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries and carotid-femoral pulse wave velocity. We analysed men and women separately while adjusting for significant covariates, including age, mean arterial pressure, heart rate, current smoking, alcohol intake and use of antihypertensive drugs. RESULTS: Before and after adjustment, arterial diameter increased with BMI in all territories, with an opposite trend for arterial distensibility. In men and women, the relationships of brachial and femoral properties with BMI were consistent across the whole age range. In men and women, carotid distensibility decreased more with BMI at young than old age. In middle-aged and older women, but not in men of any age, pulse wave velocity increased with higher BMI. CONCLUSIONS: Across a wide age range, the diameter and stiffness of muscular arteries increased with higher BMI. In elastic arteries, the relationship between arterial stiffness and BMI was more complex and varied with sex and age. The mechanisms underlying the influence of adiposity on the properties of muscular and elastic arteries and the reversibility of these associations by weight reduction at young age need further clarification.

Epistatic interaction between alpha- and gamma-adducin influences peripheral and central pulse pressures in white Europeans.

BACKGROUND: Adducin is a membrane skeleton protein consisting of alpha- and beta- or alpha- and gamma-subunits. Mutations in alpha- and beta-adducin are associated with hypertension. In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding alpha-adducin (Gly460Trp), beta-adducin (C1797T) and gamma-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness. METHODS: We measured peripheral and central PP by conventional sphygmomanometry and applanation tonometry, respectively. We randomly recruited 642 subjects (162 nuclear families and 70 unrelated individuals) from three European populations. In multivariate analyses, we used generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: Peripheral and central PP averaged 46.1 and 32.6 mmHg, respectively. Among carriers of the alpha-adducin Trp allele, peripheral and central PP were 5.8 and 4.7 mmHg higher in gamma-adducin GG homozygotes than in their AA counterparts, due to an increase in systolic pressure. gamma-Adducin GG homozygosity was associated with lower urinary Na/K ratio among alpha-adducin Trp allele carriers and with higher urinary aldosterone excretion among alpha-adducin GlyGly homozygotes. Sensitivity analyses in founders and offspring separately, and tests based on the transmission of the gamma-adducin G allele across families, confirmed the interaction between the alpha- and gamma-adducin genes. CONCLUSIONS: In alpha-adducin Trp allele carriers, peripheral and central PP increased with the gamma-adducin G allele. This epistatic interaction is physiologically consistent with the heterodimeric structure of the protein and its influence on transmembranous sodium transport.

Quality of life and antihypertensive effect with nebivolol and losartan.

BACKGROUND: Quality of life and antihypertensive effect, two important therapeutic goals, were determined with the third generation beta-blocker nebivolol and the angiotensin receptor blocker losartan are compared. METHODS: In a double-blind, randomized, parallel group study 314 patients with hypertension were treated for 12 weeks with 5 mg of nebivolol or 50 mg of losartan once daily. If after 6 weeks diastolic blood pressure (BP) was not normalized 12.5 mg of hydrochlorothiazide once daily was added. Effects of treatment were compared using analysis of variance. RESULTS: Both drugs decreased systolic BP similarly. The decrease in diastolic BP was greater (P < .0001) with nebivolol (-12 mm Hg after 6 and 12 weeks) than with losartan (-8 and -10 mm Hg after 6 and 12 weeks, respectively). Quality of life parameters did not differ between the two treatments. This was true after 6 and 12 weeks of treatment and results did not change when corrected for different effects on BP. Aspects of quality of life including questions on sexual function did not differ between the two treatments except for headache occurring less frequently (P < .05) in patients on nebivolol monotherapy at 6 weeks. CONCLUSIONS: At advocated doses nebivolol and losartan decrease systolic BP similarly, whereas the decrease in diastolic BP was slightly greater with nebivolol. Overall quality of life parameters did not differ between nebivolol and losartan. The effect on sexual function did not differ between the two treatments and less patients had headache with nebivolol than with losartan after 6 weeks of monotherapy.

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.