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Copyright © 2021 The Author(s). Pulse wave velocity, a common metric of arterial stiffness, is an established predictor for cardiovascular events and mortality. However, its intrinsic pressure-dependency complicates the discrimination of acute and chronic impacts of increased blood pressure on arterial stiffness. Cardio-ankle vascular index (CAVI) represented a significant step towards the development of a pressure-independent arterial stiffness metric. However, some potential limitations of CAVI might render this arterial stiffness metric less pressure-independent than originally thought. For this reason, we later introduced CAVI0. Nevertheless, advantages of one approach over the other are left debated. This review aims to shed light on the pressure (in)dependency of both CAVI and CAVI0. By critically reviewing results from studies reporting both CAVI and CAVI0 and using simple analytical methods, we show that CAVI0 may enhance the pressure-independent assessment of arterial stiffness, especially in the presence of large inter-individual differences in blood pressure. European Union’s Horizon 2020 Research and Innovation program (grant 793805 to B.S.).

Aims CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis. Methods We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SDCGM] and CGM-assessed CV [CVCGM]) and time in range (TIRCGM) with carotid–femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima–media thickness, ankle–brachial index and circumferential wall stress via multiple linear regression. Results Higher SDCGM was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SDCGM [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSGCGM), SDCGM and MSGCGM contributed similarly to cf-PWV (respective standardised regression coefficients [st.βs] and 95% CIs of 0.065 [−0.018, 0.167], p = 0.160; and 0.059 [−0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CVCGM (B [95% CI] per 10% CVCGM: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIRCGM (B [95% CI] per 10% TIRCGM: −0.145 m/s [−0.252, −0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures. Conclusions Our findings show that greater daily glucose variability and lower TIRCGM are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIRCGM to prevent CVD. Graphical abstract

Ex vivo characterisation of arterial biomechanics enables detailed discrimination of the various cellular and extracellular contributions to arterial stiffness. However, ex vivo biomechanical studies are commonly performed under quasi-static conditions, whereas dynamic biomechanical behaviour (as relevant in vivo) may differ substantially. Hence, we aim to (1) develop an integrated set-up for quasi-static and dynamic biaxial biomechanical testing, (2) quantify set-up reproducibility, and (3) illustrate the differences in measured arterial stiffness between quasi-static and dynamic conditions. Twenty-two mouse carotid arteries were mounted between glass micropipettes and kept fully vasodilated. While recording pressure, axial force (F), and inner diameter, arteries were exposed to (1) quasi-static pressure inflation from 0 to 200 mmHg; (2) 300 bpm dynamic pressure inflation (peaking at 80/120/160 mmHg); and (3) axial stretch (λz) variation at constant pressures of 10/60/100/140/200 mmHg. Measurements were performed in duplicate. Single-point pulse wave velocities (PWV; Bramwell-Hill) and axial stiffness coefficients (cax = dF/dλz) were calculated at the in vivo value of λz. Within-subject coefficients of variation were ~ 20%. Dynamic PWVs were consistently higher than quasi-static PWVs (p cax increased with increasing pressure. We demonstrated the feasibility of ex vivo biomechanical characterisation of biaxially-loaded murine carotid arteries under pulsatile conditions, and quantified reproducibility allowing for well-powered future study design.

Objectives: When assessing arterial stiffness, heart rate (HR) and blood pressure (BP) are potential confounders. It appears that the HR/BP dependences of pulse wave velocity (PWV) and distensibility are different, even though both assess arterial stiffness. This study aims to compare aortic PWV as measured using pulse transit time (PWVTT) and as calculated from distensibility (PWVdist) at the same measurement site and propose a solution to the disparity in dependences of PWVTT and PWVdist. Methods: Adult anaesthetized rats (n = 24) were randomly paced at HRs 300-500 bpm, at 50 bpm steps. At each step, aortic PWVTT (two pressure-tip catheters) and PWVdist (pressure-tip catheter and ultrasound wall-tracking; abdominal aorta) were measured simultaneously while BP was varied pharmacologically. Results: HR dependence of PWVdist paradoxically decreased at higher levels of BP. In addition, BP dependence of PWVdist was much larger than that of PWVTT. These discrepancies are explained in that standard PWVdist uses an approximate derivative of pressure to diameter, which overestimates PWV with increasing pulse pressure (PP). In vivo, PP decreases as HR increases, potentially causing a PWVdist decrease with HR. Estimating the full pressure-diameter curve for each HR corrected for this effect by enabling calculation of the true derivative at diastolic BP. This correction yielded a PWVdist that shows HR and BP dependences similar to those of PWVTT. As expected, BP dependence of all PWV metrics was much larger than HR dependence. Conclusion: Measured and calculated PWV have different dependences on HR and BP. These differences are, at least in part, because of approximations made in using systolic and diastolic values to calculate distensibility.

Objective: This study demonstrates a novel method for pulse arrival time (PAT) segmentation into cardiac isovolumic contraction (IVC) and vascular pulse transit time to approximate central pulse wave velocity (PWV). Methods: 10 subjects (38 +/- 10 years, 121 +/- 12 mmHg SBP) ranging from normotension to hypertension were repeatedly measured at rest and with induced changes in blood pressure (BP), and thus PWV. ECG was recorded simultaneously with ultrasound-based carotid distension waveforms, a photoplethysmography-based peripheral waveform, noninvasive continuous and intermittent cuff BP. Central PAT was segmented into cardiac and vascular time intervals using a fiducial point in the carotid distension waveform that reflects the IVC onset. Central and peripheral PWVs were computed from (segmented) intervals and estimated arterial path lengths. Correlations with Bramwell-Hill PWV, systolic and diastolic BP (SBP/DBP) were analyzed by linear regression. Results: Central PWV explained more than twice the variability (R-2) in Bramwell-Hill PWV compared to peripheral PWV (0.56 vs. 0.27). SBP estimated from central PWV undercuts the IEEE mean absolute deviation threshold of 5 mmHg, significantly lower than peripheral PWV or PAT (4.2 vs. 7.1 vs. 10.1 mmHg). Conclusion: Cardiac IVC onset signaled in carotid distension waveforms enables PAT segmentation to obtain unbiased vascular pulse transit time. Corresponding PWV estimates provide the basis for single-site assessment of central arterial stiffness, confirmed by significant correlations with Bramwell-Hill PWV and SBP. Significance: In a small-scale cohort, we present proof-of-concept for a novel method to estimate central PWV and BP, bearing potential to improve the practicality of cardiovascular risk assessment in clinical routines.

Background Conventional measures for assessing arterial stiffness are inherently pressure dependent. Whereas statistical pressure adjustment is feasible in (larger) populations, it is unsuited for the evaluation of an individual patient. Moreover, statistical “correction” for blood pressure may actually correct for: (i) the acute dependence of arterial stiffness on blood pressure at the time of measurement; and/or (ii) the remodeling effect that blood pressure (hypertension) may have on arterial stiffness, but it cannot distinguish between these processes. METHODS We derived—assuming a single-exponential pressure–diameter relationship—3 theoretically pressure-independent carotid stiffness measures suited for individual patient evaluation: (i) stiffness index β0, (ii) pressure-corrected carotid pulse wave velocity (cPWVcorr), and (iii) pressure-corrected Young’s modulus (Ecorr). Using linear regression analysis, we evaluated in a sample of the CATOD study cohort changes in mean arterial pressure (ΔMAP) and comparatively the changes in the novel (Δβ0, ΔcPWVcorr, and ΔEcorr) as well as conventional (ΔcPWV and ΔE) stiffness measures after a 2.9 ± 1.0-year follow-up. RESULTS We found no association between ΔMAP and Δβ0, ΔcPWVcorr, or ΔEcorr. In contrast, we did find a significant association between ΔMAP and conventional measures ΔcPWV and ΔE. Additional adjustments for biomechanical confounders and traditional risk factors did neither materially change these associations nor the lack thereof. Conclusions Our newly proposed pressure-independent carotid stiffness measures avoid the need for statistical correction. Hence, these measures (β0, cPWVcorr, and Ecorr) can be used in a clinical setting for (i) patient-specific risk assessment and (ii) investigation of potential remodeling effects of (changes in) blood pressure on intrinsic arterial stiffness., Graphical Abstract Graphical Abstract

The augmentation index (AIx) is deemed to capture the deleterious effect on left ventricular (LV) work of increased wave reflection associated with stiffer arteries. However, its validity as a proxy for wave reflection magnitude has been questioned. We hypothesized that, in addition to increased wave reflection due to increased pulse wave velocity, LV myocardial shortening velocity influences AIx. Using a computational model of the circulation, we investigated the isolated and combined influences of myocardial shortening velocity vs,LV and arterial stiffness on AIx. Aortic blood pressure waveforms were characterized using AIx and the reflected wave pressure amplitude ([Formula: see text], obtained using wave separation analysis). Our reference simulation (normal vs,LV and arterial stiffness) was characterized by an AIx of 21%. A realistic reduction in vs,LV caused AIx to increase from 21 to 42%. An arterial stiffness increase, characterized by a relevant 1.0 m/s increase in carotid-femoral pulse wave velocity, caused AIx to increase from 21 to 41%. Combining the reduced vs,LV and increased arterial stiffness resulted in an AIx of 54%. In a multistep parametric analysis, both vs,LV and arterial stiffness were about equal determinants of AIx, whereas [Formula: see text] was only determined by arterial stiffness. Furthermore, the relation between increased AIx and LV stroke work was only ≈50% explained by an increase in arterial stiffness, the other factor being vs,LV. The [Formula: see text], on the other hand, related less ambiguously to LV stroke work. We conclude that the AIx reflects both cardiac and vascular properties and should not be considered an exclusively vascular parameter. NEW & NOTEWORTHY We used a state-of-the-art computational model to mechanistically investigate the validity of the augmentation index (AIx) as a proxy for (changes in) wave reflection. In contrary to current belief, we found that LV contraction velocity influences AIx as much as increased arterial stiffness, and increased AIx does not necessarily relate to an increase in LV stroke work. Wave reflection magnitude derived from considering pressure, as well as flow, does qualify as a determinant of LV stroke work.

Clinical assessment of arterial stiffness relies on noninvasive measurements of regional pulse wave velocity or local distensibility. However, arterial stiffness measures do not discriminate underlying changes in arterial wall constituent properties (e.g., in collagen, elastin, or smooth muscle), which is highly relevant for development and monitoring of treatment. In arterial stiffness in recent clinical-epidemiological studies, we systematically review clinical-epidemiological studies (2012–) that interpreted arterial stiffness changes in terms of changes in arterial wall constituent properties (63 studies included of 514 studies found). Most studies that did so were association studies (52 of 63 studies) providing limited causal evidence. Intervention studies (11 of 63 studies) addressed changes in arterial stiffness through the modulation of extracellular matrix integrity (5 of 11 studies) or smooth muscle tone (6 of 11 studies). A handful of studies (3 of 63 studies) used mathematical modeling to discriminate between extracellular matrix components. Overall, there exists a notable gap in the mechanistic interpretation of stiffness findings. In constitutive model-based interpretation, we first introduce constitutive-based modeling and use it to illustrate the relationship between constituent properties and stiffness measurements (“forward” approach). We then review all literature on modeling approaches for the constitutive interpretation of clinical arterial stiffness data (“inverse” approach), which are aimed at estimation of constitutive properties from arterial stiffness measurements to benefit treatment development and monitoring. Importantly, any modeling approach requires a tradeoff between model complexity and measurable data. Therefore, the feasibility of changing in vivo the biaxial mechanics and/or vascular smooth muscle tone should be explored. The effectiveness of modeling approaches should be confirmed using uncertainty quantification and sensitivity analysis. Taken together, constitutive modeling can significantly improve clinical interpretation of arterial stiffness findings.

Background: Vascular research demonstrated that pulse wave velocity (PWV), a measure of arterial stiffness, is inherently blood pressure dependent. Considering the hypothesized pathophysiological chain of increased arterial stiffness leading to increased blood pressure load with consequent left ventricular hypertrophy (LVH) development, we conducted a systematic review of antihypertensive and lifestyle intervention studies to determine the association between, on the one hand, changes in arterial stiffness and blood pressure, and, on the other hand, changes in left ventricular mass (LVM). Methods: Using PubMed, EMBASE, Cochrane and Web of Science, we identified 23 studies, containing 2573 patients. Studies reported changes in arterial stiffness (assessed by means of PWV), SBP, DBP and LVM index (LVMI), respectively. Results: Statistically significant reductions in SBP, PWV and LVMI were reported in 16, 14 and 20 studies, respectively. Pooled analysis of studies showed that the proportion in SBP reduction did not correlate significantly to the proportion in reductions of the other two variables. On the contrary, we found a significant positive correlation (r = 0.61, P = 0.003) between arterial stiffness and reduction of LVM, expressed as a relevant reduction in LVMI of 6.9 g/m(2) per 1.0 m/s reduction in PWV. Conclusion: Our findings provide evidence that a decrease in arterial stiffness is associated with reduction of LVM. To investigate whether there exists a causal relation between LVH due to arterial stiffness increases and in turn blood pressure load increases, future studies should strive for a multiple follow-up design and use of blood pressure independent or corrected stiffness indices.

Objective : An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time. Methods : We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 +/- 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10. Results : After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness. Conclusion : A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms.

Introduction: Patients with type 2 diabetes mellitus are at high risk to develop vascular complications resulting in high morbidity and mortality. Cocoa flavanols are promising nutraceuticals with possible beneficial vascular effects in humans. However, limited research is currently available on the vascular effects in a diabetic population with inconsistent results. Possible reasons for this inconsistency might be heterogeneity in the given intervention (dose per time and day, single dose vs. split-dose, placebo formula) and the studied population (blood pressure at baseline, duration of diabetes, use of vasoactive antihypertensive and antidiabetic drugs, sex). Therefore, we aimed to develop a randomized, double-blinded, placebo-controlled cross-over trial to investigate whether cocoa flavanols have an acute impact on blood pressure and vascular reactivity in patients with type 2 diabetes with and without arterial hypertension.Methods and Analysis: We will include participants in four groups: (i) patients with type 2 diabetes without arterial hypertension, (ii) patients with type 2 diabetes with arterial hypertension and 1 antihypertensive drug, (iii) non-diabetic participants with essential hypertension and 1 antihypertensive drug, and (iv) healthy controls. All participants will complete the same protocol on both testing days, consuming high-flavanol cocoa extract (790 mg flavanols) or placebo. Macrovascular endothelial function (flow-mediated dilation) and blood pressure will be measured before and after capsule ingestion. Forearm muscle vasoreactivity (near-infrared spectroscopy) and brachial artery blood flow (echo-doppler) will be assessed in response to a dynamic handgrip exercise test after capsule ingestion. Data will be analyzed with a random intercept model in mixed models.Clinical Trial Registration:www.Clinicaltrials.gov, identifier: NCT03722199.

PurposeTo investigate whether higher blood pressure and greater arterial stiffness are associated with the presence of macular cysts and whether this association is already present in the absence of micro-aneurysms in individuals with and without type 2 diabetes.MethodsUsing spectral domain optical coherence tomography (OCT), we performed a macular volume scan in 2647 individuals (mean age 60 ± 8 years, 50% men, 27% type 2 diabetes). The association between macular cysts and 24-hour systolic and diastolic blood pressure, pulse pressure, mean arterial blood pressure, carotid-femoral pulse wave velocity and carotid distensibility was assessed by use of logistic regression.ResultsTwenty-four hours systolic blood pressure was associated with the presence of macular cysts [OR = 1.03 (95% CI 1.00–1.05) per 1 mmHg, p = 0.03]. 24 hr pulse pressure [OR = 1.61 (95% CI 1.11–2.34) per 10 mmHg, p = 0.01] and carotid-femoral pulse wave velocity [OR = 1.16 (95% CI 1.02–1.32) per 1 m/s, p = 0.02] were associated with macular cysts, while carotid distensibility was not [OR = 1.03 (95% CI 0.96–1.11) per 1.0*10−3/kPa, p = 0.45]. Associations were similar in individuals with and without type 2 diabetes and were already present in the absence of micro-aneurysms.ConclusionTwenty-four hours systolic blood pressure, 24 hr pulse pressure and carotid-femoral pulse wave velocity are associated with the presence of OCT-detected macular cysts in individuals with and without type 2 diabetes, even in the absence of micro-aneurysms. Therefore, blood pressure and aortic stiffness are potential factors contributing to macular cysts.

Background and aims: Arterial remodelling aims at normalising circumferential wall stress (CWS). Greater CWS in the carotid artery has previously been associated with the prevalence and severity of cerebral small vessel disease, a major cause of ageing-related cognitive decline. Here we test the hypothesis that greater carotid CWS is associated with poorer cognitive performance.Methods: We studied 722 individuals (60 +/- 8 years, 55% men, 42.5% highly educated, blood pressure 137 +/- 19/77 +/- 11 mmHg, n = 197 with type 2 diabetes) who completed a neuropsychological assessment and underwent vascular ultrasound to measure the intima-media thickness (IMT) and interadventitial diameter (IAD) of the left common carotid artery at a plaque-free site. From IMT and IAD, lumen diameter (LD) was calculated. These structural measures were then combined with local carotid pulse pressure and brachial mean arterial pressure to obtain a measure of pulsatile (CWSpulsatile) and average (CWSmean) mechanical load on the vessel wall. Cognitive domains assessed were memory, executive function and attention, and processing speed.Results: After adjustment for age, sex, and education, regression analyses showed that neither CWSpulsatile nor CWSmean were associated with measures of cognitive performance (p-values >= 0.31). This null association did not differ by age or educational level, and was observed in both individuals with and without carotid plaque, diabetes and/or hypertension. In addition, none of the individual measures of carotid structure (i.e. IMT, IAD, and LD) was related to cognitive performance.Conclusions: The present cross-sectional study shows that carotid CWS is not associated with cognitive performance, at least not among relatively highly educated individuals in late middle age with adequately controlled cardiovascular risk factors. (c) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The impact of disease-related changes in the extracellular matrix (ECM) on the mechanical properties of human resistance arteries largely remains to be established. Resistance arteries from both pig and human parietal pericardium (PRA) display a different ECM microarchitecture compared with frequently used rodent mesenteric arteries. We hypothesized that the biaxial mechanics of PRA mirror pressure-induced changes in the ECM microarchitecture. This was tested using isolated pig PRA as a model system, integrating vital imaging, pressure myography, and mathematical modeling. Collagenase and elastase digestions were applied to evaluate the load-bearing roles of collagen and elastin, respectively. The incremental elastic modulus linearly related to the straightness of adventitial collagen fibers circumferentially and longitudinally (both R2 ≥ 0.99), whereas there was a nonlinear relationship to the internal elastic lamina elastin fiber branching angles. Mathematical modeling suggested a collagen recruitment strain (means ± SE) of 1.1 ± 0.2 circumferentially and 0.20 ± 0.01 longitudinally, corresponding to a pressure of ~40 mmHg, a finding supported by the vital imaging. The integrated method was tested on human PRA to confirm its validity. These showed limited circumferential distensibility and elongation and a collagen recruitment strain of 0.8 ± 0.1 circumferentially and 0.06 ± 0.02 longitudinally, reached at a distending pressure below 20 mmHg. This was confirmed by vital imaging showing negligible microarchitectural changes of elastin and collagen upon pressurization. In conclusion, we show here, for the first time in resistance arteries, a quantitative relationship between pressure-induced changes in the extracellular matrix and the arterial wall mechanics. The strength of the integrated methods invites for future detailed studies of microvascular pathologies. NEW & NOTEWORTHY This is the first study to quantitatively relate pressure-induced microstructural changes in resistance arteries to the mechanics of their wall. Principal findings using a pig model system were confirmed in human arteries. The combined methods provide a strong tool for future hypothesis-driven studies of microvascular pathologies.

Objectives:Arterial stiffness index β and cardio-ankle vascular index (CAVI) are widely accepted to quantify the intrinsic exponent (β0) of the blood pressure (BP)-diameter relationship. CAVI and β assume an exponential relationship between pressure (P) and diameter (d). We aim to demonstrate that, under this assumption, β and CAVI as currently implemented are inherently BP-dependent and to provide corrected, BP-independent forms of CAVI and β. Methods and results:In P = Prefe, usually reference pressure (Pref) and reference diameter (dref) are substituted with DBP and diastolic diameter to accommodate measurements. Consequently, the resulting exponent is not equal to the pressure-independent β0. CAVI does not only suffer from this 'reference pressure' effect, but also from the linear approximation of (dP/dd). For example, assuming β0 = 7, an increase of SBP/DBP from 110/70 to 170/120 mmHg increased β by 8.1% and CAVI by 14.3%. We derived corrected forms of β and of CAVI (CAVI0) that indeed did not change with BP and represent the pressure-independent β0. To substantiate the BP effect on CAVI in a typical follow-up study, we realistically simulated patients (n = 161) before and following BP-lowering 'treatment' (assuming no follow-up change in intrinsic β0 and therefore in actual P-d relationship). Lowering BP from 160 ± 14/111 ± 11 to 120 ± 15/79 ± 11 mmHg (p < 0.001) resulted in a significant CAVI decrease (from 8.1 ± 2.0 to 7.7 ± 2.1, p = 0.008); CAVI0 did not change (9.8 ± 2.4 and 9.9 ± 2.6, p = 0.499). Conclusion:β and CAVI as currently implemented are inherently BP-dependent, potentially leading to erroneous conclusions in arterial stiffness trials. BP-independent forms are presented to readily overcome this problem.

We developed a whole-circulation computational model by integrating a transmission line (TL) model describing vascular wave transmission into the established CircAdapt platform of whole-heart mechanics. In the present paper, we verify the numerical framework of our TL model by benchmark comparison to a previously validated pulse wave propagation (PWP) model. Additionally, we showcase the integrated CircAdapt–TL model, which now includes the heart as well as extensive arterial and venous trees with terminal impedances. We present CircAdapt–TL haemodynamics simulations of: 1) a systemic normotensive situation and 2) a systemic hypertensive situation. In the TL–PWP benchmark comparison we found good agreement regarding pressure and flow waveforms (relative errors ≤ 2.9% for pressure, and ≤ 5.6% for flow). CircAdapt–TL simulations reproduced the typically observed haemodynamic changes with hypertension, expressed by increases in mean and pulsatile blood pressures, and increased arterial pulse wave velocity. We observed a change in the timing of pressure augmentation (defined as a late-systolic boost in aortic pressure) from occurring after time of peak systolic pressure in the normotensive situation, to occurring prior to time of peak pressure in the hypertensive situation. The pressure augmentation could not be observed when the systemic circulation was lumped into a (non-linear) three-element windkessel model, instead of using our TL model. Wave intensity analysis at the carotid artery indicated earlier arrival of reflected waves with hypertension as compared to normotension, in good qualitative agreement with findings in patients. In conclusion, we successfully embedded a TL model as a vascular module into the CircAdapt platform. The integrated CircAdapt–TL model allows detailed studies on mechanistic studies on heart-vessel interaction., Author summary Arterial pulse wave characteristics show associations with left ventricular hypertrophy in clinical studies. However, in such studies, measurement and signal processing errors limit assessment of causality between wave characteristics and left ventricular hypertrophy. When validated, a computational model would allow comprehensive causality studies on heart-vessel interaction without such errors. In the present study, we integrated a novel vascular module describing wave transmission in vascular networks into the CircAdapt model of whole-heart mechanics. A benchmark comparison between our vascular module and a previously validated but more complex method, showed good agreement in terms of pressure and flow waveforms. The extended CircAdapt model is now also able to quantitatively describe vascular haemodynamics, including wave dynamics.

Greater very short- to mid-term blood pressure variability (BPV) has been associated with an increased CVD risk, especially stroke. However, this link remains incompletely understood. We hypothesized that increased arterial stiffness and maladaptive carotid arterial remodeling may underlie this association. We therefore investigated the association between very short- to mid-term systolic BPV, aortic and carotid stiffness and carotid arterial remodeling using cross-sectional data from The Maastricht Study (aged 60 ± 8 years; 53% men). Aortic (carotid-femoral pulse wave velocity, n = 1671) and carotid stiffness (ultrasonography, n = 1690) were assessed. A composite index of systolic BPV was derived by standardizing and averaging systolic within-visit, 24-hour, and 7-day BPV. We performed linear regression analyses with adjustment for age, sex, glucose metabolism status, mean arterial pressure and cardiovascular risk factors. A 1-SD greater systolic BPV was statistically significantly associated with 0.10 m/s (95%CI: 0.01 – 0.20) greater cfPWV, but not with carotid distensibility (−0.033·10-3/kPa [−0.255 – 0.190]). In addition, a 1-SD greater systolic BPV was statistically significantly associated with greater carotid circumferential wall tension (0.84 dyne/cm [0.51 – 1.17]), circumferential wall stress (0.79 kPa [0.031 – 1.27]) and intima-media thickness (8.6 μm [1.0 – 16.3]). These results are indicative of maladaptive carotid remodeling, as circumferential wall tension and stress were not normalized despite greater intima-media thickness. In conclusion, greater very short- to mid-term BPV is associated with greater aortic stiffness and maladaptive carotid arterial remodeling, but not with carotid stiffness. These findings may explain, at least partially, the increased BPV-associated CVD risk, in particular stroke.

Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown. Methods: Subjects with normal glucose metabolism (n = 1796; age: 57.9 ± 8.2 years; 43.3% men), prediabetes (n = 478; age: 61.6 ± 7.6 years; 54.0% men) and T2DM (n = 669; age: 63.0 ± 7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2 h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA 1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO. Results: Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥ 30 mg/24 h [fasting: 1.12 (95% CI: 0.97–1.29); post-OGTT: 1.19 (1.01–1.41)], eGFR < 60 mL/min/1.73 m 2 [fasting: 1.58 (95% CI: 1.38–1.82), post-OGTT: 1.57 (1.34–1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01–2.53), post-OGTT: 1.38 (0.77–2.48)]. No associations with prior CVD were found. Conclusion: Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.

Carotid-femoral pulse wave velocity (cfPWV) quantifies large artery stiffness, it is used in hemodynamic research and is considered a useful cardiovascular clinical marker. cfPWV is blood pressure (BP) dependent. Intrinsic heart rate (HR) dependency of cfPWV is unknown because increasing HR is commonly accompanied by increasing BP. This study aims to quantify cfPWV dependency on acute, sympathovagal-independent changes in HR, independent of BP. Individuals (n=52, age 40–93 years, 11 female) with in situ cardiac pacemakers or cardioverter defibrillators were paced at 60, 70, 80, 90, and 100 bpm. BP and cfPWV were measured at each HR. Both cfPWV (mean [95% CI], 0.31 [0.26–0.37] m/s per 10 bpm; P P P P P

Background Carotid artery applanation tonometry is widely used in estimating local carotid artery pressure waveforms and carotid-femoral pulse wave velocity. However, the substantial pressure applied locally to the carotid artery with applanation tonometry might well evoke a baroreceptor response, resulting in bradycardia and hypotension. Therefore, when carotid and femoral tonometry are performed sequentially, baroreceptor activation could lead to different hemodynamic conditions between carotid and femoral acquisitions. Combining those acquisitions into one pulse wave velocity measure would be erroneous. In this study, we assessed whether carotid applanation tonometry has an influence on heart rate and blood pressure. Methods In 26 hypertensive subjects, heart rate and blood pressure were assessed by continuous finger pulse waveform recording during carotid as well as femoral applanation tonometry. Both carotid and femoral acquisitions were measured in alternation and in triplicate. Median averaging over the 3 carotid and femoral measurements, respectively, was used to obtain a subject's median heart rate and blood pressure during carotid as well as femoral tonometry. Results Difference in heart rate during carotid and femoral tonometry was -0.7±2.2 bpm. Differences in systolic, pulse, and diastolic blood pressure were -0.7±6.8, -0.1±3.8, and -0.3±3.5mm Hg, respectively. All differences were statistically nonsignificant. Confidence intervals were used to calculate the maximum absolute difference at 95% certainty, which was 1.6 bpm for heart rate and ≤3.5mm Hg for all blood pressures. Conclusions We conclude that in our study, carotid artery applanation tonometry as performed by an experienced researcher did not cause clinically significant baroreceptor activation.

Prediabetes and type 2 diabetes (T2D) are associated with microvascular dysfunction (1), which may explain their increased risk of microvascular complications. However, mechanisms remain poorly understood. We investigated to what extent prediabetes- and T2D-associated microvascular dysfunction is potentially attributable to (composite indices of) hyperglycemia, insulin resistance, blood pressure, arterial stiffness, lipid profile, and/or low-grade inflammation. In the Maastricht Study (2), a T2D-enriched population-based cohort study ( n = 1,791, 49% women, aged 60 ± 8 years), we determined flicker light–induced retinal arteriolar %-dilation (1) using the Dynamic Vessel Analyzer, heat-induced skin %-hyperemia (1) using laser Doppler flowmetry, and diabetes status using the oral glucose tolerance test (normal glucose metabolism \[NGM\] \[ n = 1,040\], prediabetes [ n = 276], or T2D [ n = 475]) (Table 1). Mediating effects of composite indices on prediabetes- and T2D-associated microvascular dysfunction were estimated by linear regression. View this table: Table 1 General characteristics and retinal and skin measures for the retinal study population according to glucose metabolism status Age- and sex-adjusted analyses showed lower retinal arteriolar %-dilation in prediabetes (B = −0.16 [95% CI –0.53; 0.21]), with further deterioration in T2D (B …

Background: Exaggerated exercise systolic blood pressure (SBP) is a modifiable risk factor associated with vascular dysfunction. Vascular dysfunction may contribute to the development of late-life depression, but the association between exercise SBP and incident depressive symptoms is unknown. Therefore, we investigated whether an exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time. Methods: Longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2,121; 51.3% men; age 59.5 ± 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on 4 standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 minutes after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of > = 10. Results: After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A1 standard deviation higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms (hazard ratio: 1.27 [95% confidence interval: 1.04–1.54]). Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness. Conclusion: A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms.

Greater very short- to midterm blood pressure variability (BPV) has been associated with an increased cardiovascular disease risk, especially stroke. However, this link remains incompletely understood. We hypothesized that increased arterial stiffness and maladaptive carotid arterial remodeling may underlie this association. We, therefore, investigated the association between very short- to midterm systolic BPV, aortic and carotid stiffness and carotid arterial remodeling using cross-sectional data from The Maastricht Study (aged 60±8 years; 53% men). Aortic (carotid-femoral pulse wave velocity, n=1671) and carotid stiffness (ultrasonography, n=1690) were assessed. A composite index of systolic BPV was derived by standardizing and averaging systolic within-visit, 24-hour, and 7-day BPV. We performed linear regression analyses with adjustment for age, sex, glucose metabolism status, mean arterial pressure, and cardiovascular risk factors. A 1-SD greater systolic BPV was statistically significantly associated with 0.10 m/s (95% CI, 0.01-0.20) greater carotid-femoral pulse wave velocity, but not with carotid distensibility (-0.033×10

Background: Pulse wave velocity (PWV) is quantified by time difference of arrival of the blood pressure (BP) wave at two sites along the arterial bed (transit time; TT-PWV), or by combining measured arterial pressure and diameter using the Bramwell-Hill equation (BH-PWV). Besides the dependence of PWV on BP, TT-PWV also depends on heart rate (HR). The present study aimed to also quantify the dependence of BH-PWV’s on HR, as a function of diastolic BP (DBP). Methods: Adult anaesthetised rats (n = 24) were randomly paced at 300–500 bpm, at 50-bpm steps. At each step, aortic TT-PWV (two pressure-tip catheters) and BH-PWV (pressure-tip catheter and ultrasound wall-tracking; abdominal aorta) were measured simultaneously, across a pharmacologically induced DBP range of 60–110 mmHg. Data from 9142 heart beats was analysed using mixed-effects modelling. Results: HR dependence of TT-PWV increased from 0.03 m/s/100 bpm at DBP = 60 mmHg to 0.06 m/s/100 bpm at DBP = 110 mmHg (both p ≤ 0.023). HR dependence of BH-PWV was 0.11 m/s/100 bpm at DBP = 60 and 85 mmHg, but paradoxically decreased to 0 at DBP = 110 mmHg (p = 0.686). This decrease in dependence is explicable in that standard BH-PWV uses an approximate derivative of pressure to diameter, which overestimates PWV with increasing pulse pressure (PP). PP decreases as HR increases, potentially causing a BH-PWV decrease with HR. This effect can be overcome by estimating the full pressure-diameter curve for each HR, and calculating the true derivative at DBP, yielding a BH-PWV that no longer shows significant HR dependence (p ≥ 0.076 at all DBPs). Conclusions: BH-PWV and TT-PWV show a different HR dependence, affected by DBP.

Objective: The mechanisms associating (pre)diabetes and cardiovascular disease (CVD) are incompletely understood. We hypothesize that greater blood pressure variability (BPV) may underlie this association, due to its associationwith (incident) CVD. Therefore, we investigated the association between (pre)diabetes and very short-term to mid-term BPV, that is within-visit, 24-h and 7-day BPV.Methods: Cross-sectional data from The Maastricht Study [normal glucose metabolism (NGM), n¼1924; prediabetes, n¼511; type 2 diabetes mellitus (T2DM), n¼975; 51%men, aged 608 years]. We determined SD for within visit BPV (n¼3244), average real variability for 24-h BPV (n¼2699) day (0900–2100 h) and night (0100–0600 h) separately, and SD for 7-day BPV (n¼2259). Differences inBPV as compared with NGM were assessed by multiple linear regressions with adjustment for potential confounders. Results: In T2DM, the average systolic/diastolic values of within-visit, 24-h and 7-day BPV were 4.8/2.6, 10.5/7.3 and 10.4/6.5 mmHg, respectively, and in prediabetes 4.9/ 2.6, 10.3/7.0 and 9.4/5.9 mmHg, respectively. T2DM was associated with greater nocturnal systolic BPV [0.42mmHg (95% confidence interval: 0.05–0.80)], and greater 7-daysystolic [0.76mmHg (0.32–1.19)] and diastolic BPV [0.65mmHg (0.29–1.01)], whereas prediabetes was associated with greater within-visit systolic BPV only [0.35mmHg (0.06–0.65)], as compared with NGM. Conclusion: Both T2DM and prediabetes are associated with slightly greater very short-term to mid-term BPV, which may, according to previous literature, explain a small part of the increased CVD risk seen in (pre)diabetes.Nevertheless, these findings do not detract from the fact that very short-term to mid-term BPV is substantial and important in individuals with and without (pre)diabetes.

Pulse wave velocity (PWV), a marker of arterial stiffness, is known to change instantaneously with changes in blood pressure. In this mini-review, we discuss two main approaches for handling the blood pressure dependence of PWV: (1) converting PWV into a pressure-independent index, and (2) correcting PWV per se for the pressure dependence. Under option 1, we focus on cardio-ankle vascular index (CAVI). CAVI is essentially a form of stiffness index β - CAVI is estimated for a (heart-to-ankle) trajectory, whereas β is estimated for a single artery from pressure and diameter measurements. Stiffness index β, and therefore also CAVI, have been shown to theoretically exhibit a slight residual blood pressure dependence due to the use of diastolic blood pressure instead of a fixed reference blood pressure. Additionally, CAVI exhibits pressure dependence due to the use of an estimated derivative of the pressure-diameter relationship. In this mini-review, we will address CAVI's blood pressure dependence theoretically, but also statistically. Furthermore, we review corrected indices (CAVI0 and β0) that theoretically do not show a residual blood pressure dependence. Under option 2, three ways of correcting PWV are reviewed: (1) using an exponential relationship between pressure and cross-sectional area, (2) by statistical model adjustment, and (3) through reference values or rule of thumb. Method 2 requires a population to be studied to characterise the statistical model, and method 3 requires a representative reference study. Given these limitations, method 1 seems preferable for correcting PWV per se for its blood pressure dependence. In summary, several options are available to handle the blood pressure dependence of PWV. If a blood pressure-independent index is sought, CAVI0 is theoretically preferable over CAVI. If correcting PWV per se is required, using an exponential pressure-area relationship provides the user with a method to correct PWV on an individual basis.

Quantification of the uncertainty in constitutive model predictions describing arterial wall mechanics is vital towards non-invasive assessment of vascular drug therapies. Therefore, we perform uncertainty quantification to determine uncertainty in mechanical characteristics describing the vessel wall response upon loading. Furthermore, a global variance-based sensitivity analysis is performed to pinpoint measurements that are most rewarding to be measured more precisely. We used previously published carotid diameter–pressure and intima–media thickness (IMT) data (measured in triplicate), and Holzapfel–Gasser–Ogden models. A virtual data set containing 5000 diastolic and systolic diameter–pressure points, and IMT values was generated by adding measurement error to the average of the measured data. The model was fitted to single-exponential curves calculated from the data, obtaining distributions of constitutive parameters and constituent load bearing parameters. Additionally, we (1) simulated vascular drug treatment to assess the relevance of model uncertainty and (2) evaluated how increasing the number of measurement repetitions influences model uncertainty. We found substantial uncertainty in constitutive parameters. Simulating vascular drug treatment predicted a 6% point reduction in collagen load bearing (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$L_\mathrm {coll}$$\end{document}Lcoll), approximately 50% of its uncertainty. Sensitivity analysis indicated that the uncertainty in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$L_{\mathrm {coll}}$$\end{document}Lcoll was primarily caused by noise in distension and IMT measurements. Spread in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$L_{\mathrm {coll}}$$\end{document}Lcoll could be decreased by 50% when increasing the number of measurement repetitions from 3 to 10. Model uncertainty, notably that in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$L_{\mathrm {coll}}$$\end{document}Lcoll, could conceal effects of vascular drug therapy. However, this uncertainty could be reduced by increasing the number of measurement repetitions of distension and wall thickness measurements used for model parameterisation.

Objective: In type 2 diabetes (T2D), increased arterial stiffening results from accelerated arterial wall matrix remodeling. The associated structural alterations modify the pressure dependency of arterial stiffness, which can be quantified by the systolic-diastolic difference in carotid pulse wave velocity (delta PWV). We evaluated the association between T2D and dPWV as marker for matrix remodeling and whether dPWV may contain additional information beyond carotid stiffness (cPWV).Methods: In 746 individuals from The Maastricht Study, 415 with normal glucose metabolism; 126 with prediabetes; and 205 with T2D, carotid pulse wave velocity (cPWV) and dPWV were determined by ultrasonography and tonometry. Multiple linear regression analyses were used to investigate associations of glucose metabolism status (with normal glucose metabolism as reference) with cPWV and dPWV, adjusting for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, and dPWV or cPWV as appropriate.Results: After adjustment for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, T2D was associated with greater cPWV [beta(95% confidence interval) 0.376 (0.119; 0.632)] and delta PWV [0.301 (0.013; 0.589)]. After additional adjustment for dPWV or cPWV, associations of T2D with cPWV and dPWV were attenuated [0.294 (0.048; 0.539) and 0.173 (-0.103; 0.449), respectively]. Prediabetes was not associated with either cPWV or dPWV.Conclusion: The systolic-diastolic difference in carotid stiffness is increased in T2D, but not prediabetes. Importantly, the association was not abolished by carotid stiffness, which suggests that systolic-diastolic difference in carotid stiffness carries additional information regarding arterial matrix remodeling.

Arterial pulse wave velocity (PWV) depends on blood pressure (BP). Correction of PWV for BP is commonly performed using a statistical approach, requiring a patient cohort. We recently developed a mechanistic, model-predictive approach to assess BP-independent changes in carotid PWV (cPWV) at the level of the individual. The goal of the present study is to compare our novel technique to conventional statistical correction, in the context of anti-cancer therapy using anti-angiogenic drugs (AADs). AADs frequently lead to a PWV increase, but also to hypertension, underlining the need for BP correction of PWV measurements. We obtained carotid artery systolic and diastolic cross-sectional areas (echotracking) and corresponding BPs (tonometry) in 48 patients before starting AAD treatment (sorafenib/sunitinib), and at four follow-up visits spaced 2 weeks apart. For each patient, we derived cPWV and a baseline single-exponential BP cross-sectional area curve. Based on these baseline curves and follow-up BPs, we predicted cPWV at follow-up due to BP. By comparing predicted and measured cPWVs at follow-up, we assessed the BP-independent cPWV increase. In the same way, we assessed whether diastolic cross-sectional area (A(d)) changed beyond the BP-induced amount. The AAD-induced BP-independent increase in cPWV was 0.43(0.09,0.77) ms(-1) (mean (95% CI), P=0.014, mechanistic approach) and 0.48(0.14,0.82) ms(-1) (P=0.006, statistical approach). Ad increased with 1.92(0.93,2.92) mm(2) (P

Objectives: Arterial stiffness index β and cardio-ankle vascular index (CAVI) are widely accepted to quantify the blood pressure (BP)-independent, intrinsic exponent (β0) of the BP-diameter relationship. CAVI and β assume an exponential relationship between pressure (P) and diameter (d). We aim (1) to demonstrate that, under this assumption, β and CAVI as currently implemented are inherently BP-dependent and (2) to provide corrected, BP-independent forms of CAVI and β. Methods and results: In P=Pref*exp[β0(d/dref−1)], usually reference pressure (Pref) and reference diameter (dref) are substituted with diastolic BP and diameter to accommodate measurements. Consequently, the resulting exponent is not equal to the pressure-independent β0. CAVI does not only suffer from this reference pressure effect, but also from the approximation of dP/dd. For example, assuming β0=7, an increase of systolic/diastolic BP from 110/70 to 170/120 mmHg increased β by 8.1% and CAVI by 14.3%. We derived corrected forms of β and of CAVI (CAVI0) that did not change with BP and represent the pressure-independent β0. To substantiate the BP effect on CAVI in a typical follow-up study, we realistically simulated patients (n=161) before and following BP-lowering treatment (assuming no follow-up change in intrinsic β0 and therefore in actual P-d relationship). Lowering BP from 160±14/111±11 to 120±15/79±11 mmHg (p

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 (Delta PWV) between systolic and diastolic (cPWV(d)) carotid pulse wave velocity. Biomechanically, a greater Delta PWV implies greater increases in left ventricular afterload with physical activity. Therefore, we hypothesized, that Delta PWV is more strongly associated with left ventricular mass index (LVMI) than aPWV and cPWV(d). Methods: In 1776 healthy individuals from the Asklepios cohort (age 35-55 years), Delta PWV was obtained from combined carotid artery ultrasound and tonometry recordings. Multiple linear regression analysis was performed to investigate the associations of Delta PWV, cPWV(d) and aPWV with LVMI, adjusting for age, sex, mean blood pressure (MBP), central pulse pressure, and other possible confounders. Results: DPWV was 2.4 +/- 1.2 m/s (mean +/- SD), ranging from 0.8 m/s, indicating almost constant arterial stiffness over the cardiac cycle, to 4.4 m/s, reflecting substantial pressure dependency. Delta PWV was significantly associated with LVMI (beta of 2.46 g/m(1.7) per m/s, P < 0.001), even after full adjustment (beta of 0.56 g/m(1.7) per m/s, P = 0.03). cPWV(d) and aPWV had clear crude associations with LVMI (P < 0.001), but lost significance after adjustment (beta of -0.48 and -0.33 g/m(1.7) 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.

The hollow-fibre oxygenator is a key component of any extracorporeal circuit used to provide cardiopulmonary bypass (CPB) during open-heart surgery. Since the oxygenator is placed downstream of the pump, the energy losses over it have a direct impact on the quality of pulsatile pressure and flow waveforms. The objective of this study was to describe the effects of hydrodynamic characteristics of the oxygenator on energy transfer during pulsatile, normothermic CPB. Twenty-three adult patients scheduled for coronary bypass surgery were divided randomly into two groups, using either an oxygenator (Group 1) with a relatively high-resistance and low-compliance (2079 ± 148 dyn.s.cm-5 and 0.00348 ± 0.00071 ml.mmHg-1, respectively) or an oxygenator (Group 2) with a relatively low-resistance and high-compliance (884 ± 464 dyn.s.cm-5 and 0.01325 ± 0.00161 ml .mmHg-1, respectively). During perfusion, pre- and post-oxygenator pressures, radial artery pressure, and blood flow were recorded simultaneously. A 32% decline of mean pressure was observed in Group 1 and a 16% decline in Group 2 (p

OBJECTIVE: The current study was conducted to investigate whether greater arterial stiffening is already present in normolipidemic relatives of patients with familial combined hyperlipidemia (FCHL), as compared with healthy controls, and to establish the factors that are associated with arterial stiffness in comparison with markers of atherosclerosis. METHODS: Seventy-seven FCHL patients, 121 normolipidemic relatives and 72 spouses (controls) underwent ultrasound examination of the common carotid artery to determine the presence of plaques and the degree of arterial stiffness, expressed as stiffness index alpha. RESULTS: Age-adjusted and sex-adjusted analyses revealed that the arterial stiffness index alpha and prevalence of plaques were higher in normolipidemic relatives when compared with spouses, but lower than in FCHL patients (P

Pulse wave velocity ( PWV ) provides information about the mechanical properties of the vessel: the stiffer the artery is, the higher the PWV will be. PWV measured over a short arterial segment facilitates direct characterization of local wall properties corrected for prevailing pressure without the necessity of measuring pulse pressure locally. Current methods for local PWV assessment have a poor precision, but it can be improved by applying linear regression to a characteristic time-point in distension waveforms as recorded simultaneously by multiple M-line ultrasounds. We investigated the precision of this method in a phantom scaled according to realistic in vivo conditions. Special attention was paid to the identification of the foot of the wave, using the maximum of the second derivative, the intersecting tangent and the 20% threshold method. Before foot detection, the distension waveforms were subjected to preprocessing with various filters. The precision of the maximum of the second derivative had a coefficient of variation ( CV ) of 0.45% and 10.45% for an eighth and second order low pass filter, respectively. The intersecting tangent and the threshold method were less sensitive to filtering; the CV s were 0.66% and 0.68% for the high order filter and 2.36% and 1.43% for the low order filter, respectively. We conclude that foot detection by a threshold of 20% or by the tangent method are more suitable to identify the foot of the wave to measure local PWV . Both methods are less sensitive to (phase) noise than the maximum of the second derivative method and exhibit good precision with a CV of less than 1%. (E-mail: A.Hoeks@BF.Unimaas.nl )

Aging has a profound influence on arterial wall structure and function. We have previously reported the relationship among pulse wave velocity, age, and blood pressure in hypertensive subjects. In the present study, we aimed for a quantitative interpretation of the observed changes in wall behavior with age using a constitutive modeling approach. We implemented a model of arterial wall biomechanics and fitted this to the group-averaged pressure-area ( P-A) relationship of the “young” subgroup of our study population. Using this model as our take-off point, we assessed which parameters had to be changed to let the model describe the “old” subgroup’s P-A relationship. We allowed elastin stiffness and collagen recruitment parameters to vary and adjusted residual stress parameters according to published age-related changes. We required wall stress to be homogeneously distributed over the arterial wall and assumed wall stress normalization with age by keeping average “old” wall stress at the “young” level. Additionally, we required axial force to remain constant over the cardiac cycle. Our simulations showed an age-related shift in pressure-load bearing from elastin to collagen, caused by a decrease in elastin stiffness and a considerable increase in collagen recruitment. Correspondingly, simulated diameter and wall thickness increased by about 20 and 17%, respectively. The latter compared well with a measured thickness increase of 21%. We conclude that the physiologically realistic changes in constitutive properties we found under physiological constraints with respect to wall stress could well explain the influence of aging in the stiffness-pressure-age pattern observed.

Flow-mediated dilation is aimed at normalization of local wall shear stress under varying blood flow conditions. Blood flow velocity and vessel diameter are continuous and opposing influences that modulate wall shear stress. We derived an index FMDv to quantify wall shear stress normalization performance by flow-mediated dilation in the brachial artery. In 22 fasting presumed healthy men, we first assessed intra- and inter-session reproducibilities of two indices pFMDv and mFMDv, which consider the relative peak and relative mean hyperemic change in flow velocity, respectively. Second, utilizing oral glucose loading, we evaluated the tracking performance of both FMDv indices, in comparison with existing indices [i.e., the relative peak diameter increase (%FMD), the peak to baseline diameter ratio (Dpeak/Dbase), and the relative peak diameter increase normalized to the full area under the curve of blood flow velocity with hyperemia (FMD/shearAUC) or with area integrated to peak hyperemia (FMD/shearAUC_peak)]. Inter-session and intra-session reproducibilities for pFMDv, mFMDv and %FMD were comparable (intra-class correlation coefficients within 0.521–0.677 range). Both pFMDv and mFMDv showed more clearly a reduction after glucose loading (reduction of ~45%, p≤0.001) than the other indices (% given are relative reductions): %FMD (~11%, p≥0.074); Dpeak/Dbase (~11%, p≥0.074); FMD/shearAUC_peak (~20%, p≥0.016) and FMD/shearAUC (~38%, p≤0.038). Further analysis indicated that wall shear stress normalization under normal (fasting) conditions is already far from ideal (FMDv << 1), which (therefore) does not materially change with glucose loading. Our approach might be useful in intervention studies to detect intrinsic changes in shear stress normalization performance in conduit arteries.

Background:Arterial stiffness measures such as pulse wave velocity (PWV) have a known dependence on actual blood pressure, requiring consideration in cardiovascular risk assessment and management. Given the impact of ageing on arterial wall structure, the pressure-dependence of PWV may vary with age. Methods:Using a noninvasive model-based approach, combining carotid artery echo-tracking and tonometry waveforms, we obtained pressure-area curves in 23 hypertensive patients at baseline and after 3 months of antihypertensive treatment. We predicted the follow-up PWV decrease using modelled baseline curves and follow-up pressures. In addition, on the basis of these curves, we estimated PWV values for two age groups (mean ages 41 and 64 years) at predefined hypertensive (160/90 mmHg) and normotensive (120/80 mmHg) pressure ranges. Results:Follow-up measurements showed a near 1 m/s decrease in carotid PWV when compared with baseline, which fully agreed with our model-prediction given the roughly 10 mmHg decrease in diastolic pressure. The stiffness-blood pressure-age pattern was in close agreement with corresponding data from the 'Reference Values for Arterial Stiffness' study, linking the physical and empirical bases of our findings. Conclusion:Our study demonstrates that the innate pressure-dependence of arterial stiffness may have implications for the clinical use of arterial stiffness measurements, both in risk assessment and in treatment monitoring of individual patients. We propose a number of clinically feasible approaches to account for the blood pressure effect on PWV measurements.

Acute mitral regurgitation (MR) is present in 10% of patients presenting with cardiogenic shock. To stabilize these patients, intra-aortic balloon pumping (IABP) is recommended, but the mechanism of IABP support in these patients is unknown. This animal study was designed to describe the hemodynamic effect of intra-aortic balloon pumping during cardiogenic shock induced by acute MR. In eight calves, left ventricular pressure-volume loops, aortic and left atrial pressure, and aortic, carotid artery, and coronary blood flow were recorded. Acute MR (range 36%-79%) was created by placing a metal cage in the mitral valve. Hemodynamic data was obtained at control, during acute MR, and during acute MR with 1:1 IABP support. Acute MR caused a decrease in cardiac output (-32%, P = 0.018), blood pressure, and carotid artery flow, whereas left ventricular output (+127%, P = 0.018), end-diastolic volume, and left atrial pressure all significantly increased. Stroke work, ejection fraction, and coronary blood flow were not significantly changed, and no signs of ischemia were seen on the ECG. The IABP raised average cardiac output by 31% (P = 0.012) and significantly raised blood pressure and flow to the brain while decreasing systemic vascular resistance. Left ventricular function and mean coronary blood flow did not change, but diastolic coronary flow became more important as shown by the increase in diastolic fraction from 64% to 95%. (P = 0.028). Average MR dropped by 7.5% (P = 0.025). In conclusion, application of the IABP during acute MR lowers aortic impedance, resulting in less MR and more output toward the aorta without changing left ventricular function.

A comparative study was conducted to evaluate the feasibility of a fiber-optic sensor in invasive blood pressure measurements. Static and wide-bandwidth stimuli were offered to the fiber-optic, Millar, Baxter, and Sentron devices to measure static transfer function and transient response. Animal experiments focused on offset drift, dynamic accuracy, and electromagnetic sensitivity. Compared to the Millar, Sentron, and Baxter devices, the fiber-optic sensor had a near-identical static transfer function. Gain and offset errors were3.4% and0.25%, respectively. Hysteresis nonlinearity was0.1%. The dynamic accuracy of the fiber-optic system matched that of the Millar and Sentron systems. Time delay was1 msec. Maximum rate of change was30,000 mm Hg/sec and bandwidth was 0-150 Hz minimum. Offset drift was 0.6 +/- 0.03 mm Hg. Application of diathermy highlighted the fiber-optic sensor's excellent electromagnetic disturbance rejection. The fiber-optic system appears to be a reliable, high-fidelity pressure monitor in demanding clinical environments.

Background: We recently found in patients that the pressure dependency of arterial stiffness is age-dependent, explaining clinically observed changes in stiffness with blood pressure (BP) lowering. Pulse wave velocity, BP and age found in the Reference Values for Arterial Stiffness Collaboration show a corresponding pattern. We hypothesised that the impact of age on the pressure-dependency of arterial stiffness actually reflects changes in wall constituent properties and adaptation to mechanical stress Methods and results: We applied a constitutive model of arterial wall biomechanics (Zulliger, AJP-Heart 2004) to simulate ageing, based on detailed pressure-area curves obtained in our younger (mean age 40 yrs, n=6) and older (65 yrs, n=7) hypertensive patients. Ageing was simulated by adapting the model (initially fitted to the "young" pressure-area curve) to fit the "old" curve (Figure); allowing for elastin degradation, collagen rearrangement and wall thickness adaptation, but not for changes in fractional volumes. The simulation showed a physiologically significant transfer of pressure-load bearing from elastin to collagen, caused by a 40% loss in elastin stiffness and a 5-fold increase in collagen recruitment (Table). Presuming normalisation and homogeneous distribution of wall stress with ageing, the predicted increase in wall thickness was in accordance with intima-media thickness Reference Values (2010 data; 25-yr increment, corresponding risk category). Conclusion: Ageing influences observed arterial stiffness values at given blood pressures through underlying changes in the properties and mechanical loading of arterial wall constituents.

Background Left-ventricular end-systolic elastance (Ees) is an index of cardiac contractility, but the invasive nature of its assessment has limited perioperative application. We explored the feasibility of a minimally invasive method of Ees estimation for perioperative assessment of cardiac function and evaluated the suitability of phenylephrine as a loading intervention. Methods In 17 surgical patients, Ees was determined as the slope of the end-systolic pressure–volume relation, which was obtained from non-invasive or invasive continuous arterial pressure measurements and left-ventricular volume determinations using transoesophageal echocardiography (TOE). Ees was determined using as loading interventions preload reduction by inferior vena cava compression (IVCC) and afterload increase by phenylephrine administration. Results Median invasive Ees determined with phenylephrine estimated 1.05 (0.59–1.21) mm Hg ml −1 and with IVCC 0.58 (0.31–1.13) mm Hg ml −1 . Bland–Altman analysis to evaluate the level of agreement between minimally invasive and invasive Ees estimation revealed a bias of −0.03 (0.12) mm Hg ml −1 with limits of agreement from −0.27 to 0.21 mm Hg ml −1 and the percentage error was 33%. Agreement between Ees obtained with phenylephrine and IVCC revealed a bias of 0.15 (0.69) mm Hg ml −1 with limits of agreement from −1.21 to 1.51 mm Hg ml −1 and a percentage error of 149%. Conclusions It is feasible to determine Ees combining continuous non-invasive arterial pressure measurements and left-ventricular volume determinations with TOE. However, administration of phenylephrine cannot substitute IVCC as a loading intervention, indicating that estimation of Ees in the intraoperative setting remains a challenge.

Results: As expected, clinic blood pressure values and media to lumen ratio were higher in essential hypertensive patients than in normotensive controls. Fibronectin media content was significantly greater in essential hypertensive patients (7.41 2.28 %), compared with normotensive controls (5.62 0.40, P

Arterial stiffening plays an important role in the development of hypertension and cardiovascular diseases. The intrinsically nonlinear (ie, pressure-dependent) elastic behavior of arteries may have serious consequences for the accuracy and interpretation of arterial stiffness measurements and, ultimately, for individual patient management. We determined aortic pressure and common carotid artery diameter waveforms in 21 patients undergoing cardiac catheterization. The individual pressure-area curves were described using a dual exponential analytic model facilitating noise-free calculation of incremental pulse wave velocity. In addition, compliance coefficients were calculated separately in the diastolic and systolic pressure ranges, only using diastolic, dicrotic notch, and systolic data points, which can be determined noninvasively. Pulse wave velocity at systolic pressure exhibited a much stronger positive correlation with pulse pressure ( P P =0.012) than pulse wave velocity at diastolic pressure. Patients with an elevated systolic blood pressure (>140 mm Hg) had a 2.5-times lower compliance coefficient in the systolic pressure range than patients with systolic blood pressures P =0.002). Most importantly, some individuals, with comparable age or pulse pressure, had similar diastolic but discriminately different systolic pulse wave velocities and compliance coefficients. We conclude that noninvasive assessment of arterial stiffness could and should discriminate between systolic and diastolic pressure ranges to more precisely characterize arterial function in individual patients.

Local pulse wave velocity, a direct measure of arterial stiffness, can be measured using the systolic foot of the pressure waveform as the time reference point. The accuracy and precision of systolic foot identification, which may be disturbed by early wave reflections, heavily affects pulse wave transit time measurements. We investigated within subjects the existence of early wave reflections and their interference with systolic foot identification.Fourteen ultrasound-derived distension waveforms, spaced over 16.4 mm, were simultaneously recorded in the CCA 3 cm proximal of the bifurcation of 12 young subjects. The second derivatives of the distension waveforms were calculated to identify the systolic foot and an inflection point preceding systolic peak distension. Pulse wave transit time was calculated as the time difference between the most proximal and most distal time-point, using either the systolic foot or the inflection point. The time to reflection (DeltaTSF_IP) was defined as the time difference between the systolic foot and the inflection point.Both transit times (TT SF and TT IP) could be determined with good intrasubject precision: 0.7 and 1.4 ms, respectively. The systolic foot is running forward, TT SF = 3.1 +/- 0.9 ms, whereas the inflection point appears to run backward, TT IP = -3.9 +/- 1.4 ms. DeltaTSF_IP was 44.3 +/- 8.8 ms.Despite the good intrasubject reproducibility, confluence of incident and reflected waves disturbs identification and discrimination of the systolic foot and the inflection point, resulting in biased estimates. Therefore both points are unsuitable for local pulse transit time measurements in the common carotid artery.