Luc Van Bortel

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.

Single‐dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

AIMSnAnacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib.nnnMETHODSnSafety, tolerability, anacetrapib concentrations and CETP activity were evaluated.nnnRESULTSnAnacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure.nnnCONCLUSIONSnWhereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

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 (nu200a=u200a1489; 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 &bgr;s, 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.

Impact of Radial Artery Pressure Waveform Calibration on Estimated Central Pressure Using a Transfer Function Approach

To the Editor:nnIt is with great interest that we have read the excellent work of McEniery et al1 on the variability of the relation between central and brachial pulse pressure (pressure amplification), assessed in >10 000 subjects. We were, however, a little surprised about the magnitude of the central-to-brachial pressure amplification, which is in the order of 1.38 for the entire population (estimated from their Table 1). We hypothesize that these high values arise from the use of central aortic pressure curves synthesized from radial pressure tracings, with the most important factor not being the generalized pressure transfer function …

Polypharmacy in a Belgian cohort of community-dwelling oldest old (80+)

Abstract Objectives: Polypharmacy is highly prevalent among older people (65+), but little is known on the medication use of the oldest old (80+). This study explores the medication use of the Belgian community-dwelling oldest old in relation to their demographic, clinical and functional characteristics. Methods: Baseline data was used from the BELFRAIL study; a prospective, observational population-based cohort of Belgian community-dwelling patients (80+). General practitioners recorded clinical problems and medications. Medications were coded by the Anatomic Therapeutic Chemical classification. Results: Participants’ (n = 503) mean age was 84.4 years (range 80–102) and 61.2% was female. Median chronic medication use was 5 (range 0–16). Polypharmacy (≥5 medications) was high (57.7%), with excessive polypharmacy (≥10 medications) in 9.1%. Most commonly used medication group were antithrombotics, but also benzodiazepines and antidepressants were frequently consumed. Demographics related to polypharmacy (univariate analysis) were female gender, low education and moderate alcohol use. Age, care dependency and cognitive impairment showed no association with polypharmacy. In multivariate analysis, the predominant association with polypharmacy was found for multimorbidity (OR 1.78, 95% CI 1.5–2.1), followed by depression (OR 3.7, 95% CI 4.4–9.7) and physical activity (OR 0.8, 95% CI 0.7–0.9). Conclusions: Polypharmacy was high among Belgian community-dwelling oldest old (80+). Determinants of polypharmacy were interrelated, but dominated by multimorbidity. On top of the burden of multimorbidity, polypharmacy was independently associated with less physical activity, and with depressive symptoms.

Association of menopause and hormone replacement therapy with large artery remodeling

OBJECTIVEnTo evaluate the remodeling of large arteries according to age at menopause, duration of menopause, and use of hormone therapy (HT).nnnDESIGNnA cross-sectional study consisting of baseline measurements of a multicentric randomized trial were used to evaluate arterial parameters.nnnSETTINGnThe study was conducted in France, Belgium, and the Netherlands in academic hospitals and private clinics.nnnPATIENT(S)nPostmenopausal women (n = 538) with mild hypercholesterolemia.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nCommon carotid artery intima-media thickness (CCA-IMT), central pulse pressure, and aortic stiffness (carotid-femoral pulse wave velocity) were measured and centrally controlled for quality. Multivariate regression analysis was used to assess the possible covariates associated with arterial parameters.nnnRESULT(S)nWomen were 58 ± 6 (mean ± SD) years of age with an age of 50 ± 5 at menopause and a mean duration of menopause of 8 ± 7 years. Lower age at menopause, time since menopause, and absence of HT use were independently associated with worsening of the arterial parameters. After multivariate analysis, HT was associated with a lower CCA-IMT (-40 μm [range -64 to -1]), whereas lower age at menopause and menopause duration were respectively associated with a CCA-IMT increase (25 μm/5 y and 27 μm/5 y). Similarly, values of central pulse pressure and pulse wave velocity were lower in HT users (-3.1 mm Hg [-5.1 to -0.9] and -0.31 m/s [-0.63 to -0.02], respectively) but worsened with age at menopause and menopause duration.nnnCONCLUSION(S)nThe age at menopause, the time since menopause, and the use of HT are independently associated with the thickening and stiffening of the large arteries.nnnCLINICAL TRIAL REGISTRATION NUMBERnNCT00163163.

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

PurposeBeta-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.MethodsA 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).ResultsAtosiban 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.ConclusionsThe 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.

KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers

BackgroundMitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(−related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored.ResultsKH176 was well tolerated up to and including a single dose of 800xa0mg and multiple doses of 400xa0mg b.i.d. for 7xa0Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000xa0mg and at a multiple dose of 400xa0mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000xa0mg and multiple doses of 400xa0mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000xa0ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed.ConclusionThe study deemed that KH176 is well tolerated up to single doses of 800xa0mg and multiple doses of 400xa0mg b.i.d. and has a pharmacokinetic profile supportive for a twice daily dosing. Only at high doses, KH176 causes clinically relevant changes in cardiac electrophysiology, including prolonged QTc interval and changes in T wave morphology. A Phase 2 clinical trial (100xa0mg b.i.d., orally) has been conducted recently of which the final results are expected Q1 2018.Trial registrationNCT02544217. Registered. ISRCTN43372293. Retrospectively registered.

Microwave-assisted on-spot derivatization for gas chromatography-mass spectrometry based determination of polar low molecular weight compounds in dried blood spots.

Dried blood spot (DBS) sampling and analysis is increasingly being applied in bioanalysis. Although the use of DBS has many advantages, it is also associated with some challenges. E.g. given the limited amount of available material, highly sensitive detection techniques are often required to attain sufficient sensitivity. In gas chromatography coupled to mass spectrometry (GC-MS), derivatization can be helpful to achieve adequate sensitivity. Because this additional sample preparation step is considered as time-consuming, we introduce a new derivatization procedure, i.e. microwave-assisted on-spot derivatization, to minimize sample preparation of DBS. In this approach the derivatization reagents are directly applied onto the DBS and derivatization takes place in a microwave instead of via conventional heating. In this manuscript we evaluated the applicability of this new concept of derivatization for the determination of two polar low molecular weight molecules, gamma-hydroxybutyric acid (GHB) and gabapentin, in DBS using a standard GC-MS configuration. The method was successfully validated for both compounds, with imprecision and bias values within acceptance criteria (<20% at LLOQ,u2009<15% at 3 other QC levels). Calibration lines were linear over the 10-100μg/mL and 1-30μg/mL range for GHB and gabapentin, respectively. Stability studies revealed no significant decrease of gabapentin and GHB in DBS upon storage at room temperature for at least 84 days. Furthermore, DBS-specific parameters, including hematocrit and volume spotted, were evaluated. As demonstrated by the analysis of GHB and gabapentin positive samples, microwave-assisted on-spot derivatization proved to be reliable, fast and applicable in routine toxicology. Moreover, other polar low molecular weight compounds of interest in clinical and/or forensic toxicology, including vigabatrin, beta-hydroxybutyric acid, propylene glycol, diethylene glycol, 1,4-butanediol and 1,2-butanediol, can also be detected using this method.

Proximal aortic stiffening in Turner patients may be present before dilation can be detected: a segmental functional MRI study

BackgroundTo study segmental structural and functional aortic properties in Turner syndrome (TS) patients. Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome. Cardiovascular magnetic resonance (CMR) allows segmental study of aortic elastic properties.MethodWe performed Pulse Wave Velocity (PWV) and distensibility measurements using CMR of the thoracic and abdominal aorta in 55 TS-patients, aged 13-59y, and in a control population (nu2009=u200938;12-58y). We investigated the contribution of TS on aortic stiffness in our entire cohort, in bicuspid (BAV) versus tricuspid (TAV) aortic valve-morphology subgroups, and in the younger and older subgroups.ResultsDifferences in aortic properties were only seen at the most proximal aortic level. BAV Turner patients had significantly higher PWV, compared to TAV Turner (pu2009=u20090.014), who in turn had significantly higher PWV compared to controls (pu2009=u20090.010). BAV Turner patients had significantly larger ascending aortic (AA) luminal area and lower AA distensibility compared to both controls (all pu2009<u20090.01) and TAV Turner patients. TAV Turner had similar AA luminal areas and AA distensibility compared to Controls. Functional changes are present in younger and older Turner subjects, whereas ascending aortic dilation is prominent in older Turner patients. Clinically relevant dilatation (TAV and BAV) was associated with reduced distensibility.ConclusionAortic stiffening and dilation in TS affects the proximal aorta, and is more pronounced, although not exclusively, in BAV TS patients.Functional abnormalities are present at an early age, suggesting an aortic wall disease inherent to the TS. Whether this increased stiffness at young age can predict later dilatation needs to be studied longitudinally.