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Background:Arterial stiffening is a hallmark of vascular ageing and a consequence of many diseases including diabetes mellitus. Methylglyoxal (MGO), a highly reactive α-dicarbonyl mainly formed during glycolysis, has emerged as a potential contributor to the development of arterial stiffness. MGO reacts with arginine and lysine residues in proteins to form stable advanced glycation endproducts (AGEs). AGEs may contribute to arterial stiffening by increased cross-linking of collagen within the extracellular matrix (ECM), by altering the vascular structure, and by triggering inflammatory and oxidative pathways. Although arterial stiffness is mainly determined by ECM and vascular smooth muscle cell function, the effects of MGO and MGO-derived AGEs on these structures have not been thoroughly reviewed to date. Methods and results:We conducted a PubMed search without filtering for publication date which resulted in 16 experimental and 22 clinical studies eligible for inclusion. Remarkably, none of the experimental and only three of the clinical studies specifically mentioned MGO-derived AGEs. Almost all studies reported an association between arterial stiffness and AGE accumulation in the arterial wall or increased plasma AGEs. Other studies report reduced arterial stiffness in experimental models upon administration of AGE-breakers. Conclusions:No papers published to date directly show an association between MGO or MGO-derived AGEs and arterial stiffening. The relevance of the various underlying mechanisms is not yet clear, which is particularly due to methodological challenges in the detection of MGO and MGO-derived AGEs at the molecular, intra- and pericellular, and structural levels, as well as in challenges in the assessment of intrinsic arterial wall properties at ECM- and tissue levels.

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

Hemodynamics play a central role in hemostasis and thrombosis by affecting all aspects linked to platelet functions and coagulation. In vitro flow devices are extensively used in basic research, pharmacological studies, antiplatelet agent screening, and development of diagnostic tools. Because hemodynamic conditions vary tremendously throughout the vascular tree and among different (patho)physiological processes, it is important to use flow conditions based on relevant biorheological reference ranges. Surprisingly, it is particularly difficult to find a concise overview of relevant hemodynamic parameters in various human and mouse vessels. To our knowledge, this is the first time an inventory of flow conditions in healthy, non-diseased, human and mouse vessels has been created. The objective of providing such a repertoire is to aid researchers in the field of hemostasis and thrombosis in choosing rheological conditions relevant in in vitro flow experiments and to promote harmonization of flow-based assays to facilitate comparative evaluations between studies. With reference to the human, we discuss relevant similarities and discrepancies in wall shear rates in the mouse, which are typically one order of magnitude greater in agreement with allometric scaling laws between species. Importantly, we bring the attention of the researchers to the fact that the relevant range of average wall shear rates in human arteries where clinically relevant arterial thrombosis occurs may fall as low as 100 to 200 s(-1), thus significantly overlapping with what are considered "venous" shear rates. The same range for the murine arteries used for arterial thrombosis models may significantly exceed 1000 s(-1) reaching values considered to be "pathological."

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.

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, −0.018 SD [95% CI, −0.036 to −0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, −0.089 SD [95% CI, −0.124 to −0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction.

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.

OBJECTIVE: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy.RESEARCH DESIGN AND METHODS: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors.RESULTS: The retinal microvascular diameter study population consisted of N=2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e. lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95%CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e. aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without.CONCLUSION: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.

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

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.

In a response to a Formal Comment critiquing their model for classifying individualized glucose patterns into glucotypes, these authors stand by their results and conclusions, which can be reproduced using their publicly available data, and maintain that improved algorithms for analyzing CGM data will continue to emerge and enrich the field.

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.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO-ZonMw Background The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiac exercise performance (CEP) in heart failure with preserved ejection fraction (HFpEF) remains largely unknown Purpose To elucidate the relative effects of LVDD and impaired LA function on hemodynamics at rest and on cardiac performance during exercise by performing virtual HFpEF patient simulations. Methods Using a well-validated cardiovascular system model (CircAdapt), impaired LV relaxation was simulated by increasing the rate of myocardial relaxation (tau) from 35 to 65 ms. To study the effect of moderate and sever LV myocardial stiffness increase, LV end-diastolic elastance was increased from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml, respectively. In each simulation, LV diastolic function at rest (cardiac output (CO) and heart rate (HR) of 5.1 l/min and 70 bpm, respectively) was assessed using LV ejection fraction (LVEF), mitral E/A ratio, maximum LA volume (LAV), and mean left atrial (LA) pressure (mLAP). To investigate the relative effect of these cardiac abnormalities on exercise capacity, CO and HR were gradually increased using a fixed CO-HR relationship until mLAP exceeded a threshold pressure of 35 mmHg, which was assumed to be a physiological limit of exercise intensity. Results Simulations showed that regardless of the modelled LV and LA function, LVEF was preserved (>50%). Impaired LV relaxation function was associated with decreased E/A-ratio and a small increase in mLAP at rest, regardless of LA function. Increased LV passive stiffness resulted in increased E/A-ratio, LA dilation and markedly elevated mLAP at rest, regardless of LA function (Figure: top-left). Impaired LA function resulted in reduced A-peak velocity, and increased E/A–ratio, LAV and mLAP at rest regardless of LV function (Figure: top-right) Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function, in particular when LA function is impaired (Figure: bottom). Conclusions Through simple and well-controlled variations in LV and LA function, we were able to simulate virtual HFpEF patients with a wide range of LVDD severities at rest, preserved LVEF, and reduced cardiac exercise performance. In general, our simulations suggest that increased LV passive stiffness, rather than impaired LV relaxation function, reduces exercise tolerance, especially in the presence of LA dysfunction. Abstract Figure. Simulating rest & exercise hemodynamics

Background: Arterial stiffness is a strong predictor of cardiovascular diseases and all-cause mortality [1]. Increased fasting plasma concentrations of highly reactive dicarbonyl compounds – methylglyoxal (MGO), 3-deoxyglucosone (3-DG), and/or glyoxal (GO) – may cause arterial stiffening via for mation of advanced glycation endproducts, triggering maladaptive responses in vascular tissue, e.g. elastin degradation and collagen cross-linking [2]. We assessed the cross-sectional associations between MGO, 3-DG, and GO concentrations with local carotid stiffness measures (distensibility coefficient (cDC), radius-wall thickness ratio (cRWT), pulse wave velocity (cPWV), and Young’s elastic modulus (cE) using standardized main variables. Methods: Fasting dicarbonyl concentrations were determined by ultra-performance liquid chromatography tandem mass spectrometry in EDTA plasma collected from 2275 participants (age: 60 ± 8 years, mean ± SD; 49% women, 605 with type 2 diabetes mellitus) of the Maastricht Study [3], an observational, population-based cohort study. Cross-sectional associations were assessed using multivariable linear regression analysis adjusting for age, sex, mean arterial pressure (MAP), heart rate, lifestyle factors, and medication. Since arterial stiffness measures are intrinsically pressure dependent, we additionally assessed the associations with pressure-corrected counterparts [4], instead of statistically correcting for MAP. Results: Fasting dicarbonyl concentrations were associated with arterial stiffening (smaller cDC; larger cPWV and cE) in most crude models, but not in adjusted models (Table). cRWT was associated with 3-DG, but only in the crude model. The use of pressure-corrected metrics did not materially change the final models. Model cDC cRWT cPWV cE α (95% CI) α (95% CI) α (95% CI) α (95% CI) MGO 0 –0.104(–0.145;–0.063) 0.011(–0.030;0.052) 0.103(0.062;0.144) 0.099(0.059;0.140) 1 –0.032(–0.070;0.005) 0.010(–0.032;0.052) 0.032(–0.006;0.071) 0.033(–0.007;0.072) 2 0.005(–0.029;0.039) 0.000(–0.042;0.042) –0.004(–0.039;0.030) –0.006(–0.042;0.030) 3 0.003(–0.031;0.037) 0.000(–0. 043; 0.042) –0.003(–0.038;0.032) –0.005(–0.040;0.031) 3-DG 0 –0.164(–0.205;–0.123) 0.067(0.026;0.108) 0.149(0.108;0.190) 0.171(0.131;0.212) 1 –0.102(–0.154;–0.051) 0.024(–0. 033; 0.082) 0.075(0.023;0.127) 0.093(0.039;0.147) 2 –0.037(–0.084;0.009) 0.009(–0.049;0.066) 0.012(–0.036;0.060) 0.027(–0.023;0.076) 3 –0.018(–0.065;0.029) –0. 004(–0.062; 0.054) –0.007(–0.056;0.041) 0.004(–0.045;0.054) GO 0 –0.054(–0.095;–0.013) –0.032(–0.074;0.009) 0.054(0.012;0.095) 0.038(–0.003;0.079) 1 –0.015(–0.051;0.022) –0.014(–0.055; 0.026) 0.015(–0.022;0.052) 0.008(–0.030;0.046) 2 0.002(–0.031;0.035) –0.015(–0.056;0.025) –0.002(–0.035;0.032) –0.008(–0. 042;0. 027) 3 –0.009(–0.042;0.024) –0.013(–0.053; 0.028) 0.011(–0.022;0.045) 0.005(–0.030;0.040) Model 0: crude associations. Model 1: model 0 + age, sex, and glucose metabolism status. Model 2: model 1 + mean arterial pressure and mean heart rate, and anti-hypertensive drugs. Model 3: model 2 + body mass index, smoking status, physical activity, use of lipid-modifying drugs, fasting triglycerides and total-to-high-density lipoprotein cholesterol levels, alcohol use, history of cardiovascular disease, kidney function, and Dutch healthy diet score. MGO, methylglyoxal; 3DG, 3-deoxyglucosone; GO, glyoxal; cDC, carotid distensibility coefficient; cRWT, carotid radius-wall thickness ratio; cPWV, carotid pulse wave velocity; cE, carotid Young’s elastic modulus. Significant associations (p < 0.05) printed in bold. TableAssociations between fasting plasma dicarbonyls and carotid stiffness measures Conclusion: Fasting plasma concentrations of either MGO, 3-DG, or GO are not independently associated with carotid stiffness in this cross-sectional analysis.

Background Left ventricular (LV) diastolic dysfunction, i.e. impaired LV relaxation function and/or increased LV stiffness, has been hypothesized to be responsible for at least part of the exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Yet the mechanisms remain largely unknown. Purpose To determine in silico if and how abnormal LV diastolic function causes reduction in maximum cardiac output (COmax), i.e. exercise intolerance. Methods We used a cardiovascular model (CircAdapt) to simulate the effects of impaired LV relaxation and increased LV myocardial stiffness on cardiac hemodynamics. The model was initialized using a reference simulation with hypertension (systolic blood pressure: 150 mmHg) and concentric LV hypertrophy (LV wall mass: +25%). Impaired LV relaxation was introduced by increasing tau from 35 ms to 65 ms. LV stiffness was increased by increasing LV end-diastolic elastance from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml (moderate and severe LV stiffness, respectively). In each simulation, LV ejection fraction (LVEF), E/A ratio and mean left atrial (LA) pressure (mLAP) was assessed. To evaluate the effect on exercise tolerance, COmax was determined by gradually increasing cardiac output and heart rate in a predefined manner until mLAP exceeded 35 mmHg. Results In all simulations, LVEF remained unchanged and preserved (i.e. 60%). In rest, impaired LV relaxation decreased E/A ratio from 1.1 to 0.8 (impaired filling pattern) and increased mLAP from 7.2 mmHg to 8.0 mmHg (Figure top: gray vs. orange). Total LV filling time was reduced at rest, reducing diastolic reserve capacity and thereby of COmax, by 15% compared to the reference (Figure bottom: gray vs. orange). Moderate LV stiffness increased E/A ratio to 1.1 (pseudo-normal filling pattern) and mLAP to 15.0 mmHg (Figure top: gray vs. red). COmax was reduced by 40% due to a steep increase of mLAP with exercise intensity. Severe LV stiffness increased E/A ratio to 2.2 (i.e. restrictive filling pattern), but resulted in a non-physiological mLAP of 40 mmHg at rest. However, when combining moderate LV stiffness with LA dysfunction (i.e. reduced LA contractility and increased LA stiffness) also led to restrictive filling pattern (E/A ratio >2.0) with mLAP 19 mmHg (Figure top: red vs. dashed blue). COmax reduced most severely by 53%, emphasizing the importance of LA function in LV diastolic dysfunction (Figure bottom: gray vs. dashed blue). Conclusions Through variations in LV and LA function, we linked the progression of LV diastolic dysfunction to LV and LA properties. Increased LV stiffness, more than impaired LV relaxation, is associated with substantially reduced exercise tolerance. The combination of LV and LA dysfunction led to the most severe exercise intolerance. Our unique in silico framework enables future studies to investigate other potential cardiac and vascular mechanisms underlying exercise intolerance in HFpEF. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Netherlands Organisation for Scientific Research and the Dutch Heart Foundation.

Background Arterial stiffness is an independent risk factor for cardiovascular disease and can be beneficially influenced by physical activity. However, it is not clear how an individual’s physical activity pattern over a week is associated with arterial stiffness. Therefore, we examined the associations of the amount and pattern of higher intensity physical activity with arterial stiffness. Methods and Results Data from the Maastricht Study (n=1699; mean age: 60±8 years, 49.4% women, 26.9% type 2 diabetes mellitus) were used. Arterial stiffness was assessed by carotid‐to‐femoral pulse wave velocity and carotid distensibility. The amount (continuous variable as h/wk) and pattern (categorical variable) of higher intensity physical activity were assessed with the activPAL3. Activity groups were: inactive (150 min/wk in ≤2 sessions), and regularly active (>150 min/wk in ≥3 sessions). In the fully adjusted model (adjusted for demographic, lifestyle, and cardiovascular risk factors), higher intensity physical activity was associated with lower carotid‐to‐femoral pulse wave velocity (amount: β = −0.05, 95% CI, −0.09 to −0.01; insufficiently active: β = −0.33, 95% CI, −0.55 to −0.11; weekend warrior: β = −0.38, 95% CI, −0.64 to −0.12; and regularly active: β = −0.46, 95% CI, −0.71 to −0.21 [reference: inactive]). These associations were stronger in those with type 2 diabetes mellitus. There was no statistically significant association between higher intensity physical activity with carotid distensibility. Conclusions Participating in higher intensity physical activity was associated with lower carotid‐to‐femoral pulse wave velocity, but there was no difference between the regularly actives and the weekend warriors. From the perspective of arterial stiffness, engaging higher intensity physical activity, regardless of the weekly pattern, may be an important strategy to reduce the risk of cardiovascular disease, particularly in individuals with type 2 diabetes mellitus.

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/).

Background Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA1c and other confounders. Methods IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, cardiovascular risk factors, lifestyle factors, and medication use. Results Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: − 0.026 10−3/kPa [− 0.112; 0.060]), cIMT (B: − 2.745 µm [− 5.736; 0.245]), CWSpuls (B: 0.108 kPa [− 0.054; 0.270]), retinal arteriolar average dilatation (B: − 0.022% [− 0.087; 0.043]), or heat-induced skin hyperemia (B: − 1.380% [− 22.273; 19.513]). Conclusions IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.

Objectives To investigate the utility of ultrasonic (US) perfluorohexane (PFH)-loaded monocyte imaging for detection of liver inflammation in fatty liver disease. Methods C57Bl6 mice were injected intraperitoneally with tumor necrosis factor α and assessed by US PFH-loaded monocyte imaging 3 hours later. Echogenic monocytes were injected intravenously, leading to a transient increase in liver tissue intensity on a US perfusion scan. The contrast wash-out time constant was hypothesized to reflect the degree of inflammation. Next, we evaluated US PFH-loaded monocyte imaging in Ldlr−/− mice fed a 1-week high-fat/high-cholesterol diet as model for early developing nonalcoholic steatohepatitis. Adjunct analyses included tissue markers of liver inflammation. Results Tumor necrosis factor α–injected mice showed a reduced wash-out time constant (mean ± SEM, 0.013 ± 0.003; n = 8) compared to controls (0.054 ± 0.009; n = 7; P = .0006), indicative of increased inflammatory adhesion molecule expression on the endothelium. The Ldlr−/− mice fed the high-fat/high-cholesterol diet showed liver inflammation, as reflected by increased (3- to 4-fold) infiltration of inflammatory cells and increased (3- to 4-fold) gene expression of tumor necrosis factor α, integrin αM, intracellular adhesion molecule, and vascular cell adhesion molecule. However, in these mice, no difference was detected in the wash-out time constant as assessed by US PFH-loaded monocyte imaging (high-fat/high-cholesterol, 0.050 ± 0.017; n = 5; chow, 0.048 ± 0.006; n = 6; P = .91). Conclusions Our results indicate that US PFH-loaded monocyte imaging is able to detect vascularly expressed inflammatory adhesion molecules in the mouse liver on direct endothelial stimulation. However, in our mouse model of early developing nonalcoholic steatohepatitis, we did not detect inflammation by this method, which may suggest that the time-dependent relationship between parenchymal and endothelial inflammation remains a fundamental issue to be addressed.

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.

Introduction: Pulmonary transit time (PTT) assessed with contrast-enhanced ultrasound (CEUS) is a novel tool to evaluate cardiac function. PTT represents the time for a bolus of contrast to pass from the right to the left ventricle, measured according to the indicator dilution principles using CEUS. We investigated the hypothesis that PTT is a measure of general cardiac performance in patient populations eligible for cardiac resynchronization therapy (CRT). Methods: The study population consisted of heart failure patients referred for CRT with NYHA class II–IV, left ventricular ejection fraction (LVEF)≤35% and QRS≥120 ms. CEUS, ECG, and blood were analyzed, and participants completed a quality of life questionnaire at baseline and 3 months after CRT implantation. Normalized PTT (nPTT) was calculated to compensate for the heart rate. Correlations were assessed with Pearson's or Spearman's coefficients and stratified for rhythm and NYHA class. Results: The study population consisted of 94 patients (67 men) with a mean age of 70±8.9 years. (n)PTT was significantly correlated with left ventricular parameters (rs=−.487, Ps=.475, Ps=.364, P

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.

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.

Background: Vascular research demonstrated that pulse wave velocity (PWV), a measure of arterial stiffness, is inherently blood pressure-dependent. Considering the hypothesised pathophysiological chain of increased arterial stiffness leading to increased blood pressure load with consequent left ventricle 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 LV 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), systolic- and diastolic blood pressure (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 other hand, we found a significant positive correlation (r = 0.58, p = 0.007) between arterial stiffness and LVM regression, expressed as a relevant reduction in LVMI of 6.5 g/m2 per 1.0 m/s reduction in PWV. Conclusions: Our findings provide evidence that a decrease in arterial stiffness is associated with regression of LVH. 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 followup design and use of blood pressure-independent or -corrected stiffness indices.

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.

Introduction: During ultrasound distensibility assessment of the carotid artery, the patient's head is usually rotated sideward and slightly upward to optimize visibility of the carotid segment. Head rotation may affect vessel length and thus the longitudinal strain of the arterial segment. Because the longitudinal and circumferential mechanical behaviour of an artery are intrinsically related, head rotation may influence circumferential mechanics and thereby measured distensibility. Methods: In 12 apparently healthy volunteers (age 22 ± 3 years, mean ± SD, 6 men/6 women), we investigated whether head rotation led to a change in absolute and relative distension of the common carotid artery (CCA) by performing ultrasound examinations with the head in two orientations. Additionally, CCA length was measured in both orientations with MRI to assess whether indeed a change in length occurred because of head rotation. Rotation-induced longitudinal strain was calculated from these lengths. Results: We found a significant decrease of 0.054 mm (6.8%, P = 0.001) and 0.007 (5.6%, P = 0.019) in absolute and relative distension with head rotation, respectively. MRI measurements showed a significant rotation-induced longitudinal strain of 1.7 ± 2.3% (P = 0.032). Conclusion: We conclude that consistent head rotation during a CCA ultrasound assessment causes a significant and clinically relevant bias in carotid artery distension measurements. The impact of unstandardized use of head rotation in studies with carotid distensibility as an outcome measure can therefore not be neglected; thus, standardization is highly recommendable.

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.

Item does not contain fulltext OBJECTIVES: Brachial artery flow-mediated dilation (FMD) is a popular technique to examine endothelial function in humans. Identifying volunteer and methodological factors related to variation in FMD is important to improve measurement accuracy and applicability. METHODS: Volunteer-related and methodology-related parameters were collected in 672 volunteers from eight affiliated centres worldwide who underwent repeated measures of FMD. All centres adopted contemporary expert-consensus guidelines for FMD assessment. After calculating the coefficient of variation (%) of the FMD for each individual, we constructed quartiles (n = 168 per quartile). Based on two regression models (volunteer-related factors and methodology-related factors), statistically significant components of these two models were added to a final regression model (calculated as beta-coefficient and R). This allowed us to identify factors that independently contributed to the variation in FMD%. RESULTS: Median coefficient of variation was 17.5%, with healthy volunteers demonstrating a coefficient of variation 9.3%. Regression models revealed age (beta = 0.248, P < 0.001), hypertension (beta = 0.104, P < 0.001), dyslipidemia (beta = 0.331, P < 0.001), time between measurements (beta = 0.318, P < 0.001), lab experience (beta = -0.133, P < 0.001) and baseline FMD% (beta = 0.082, P < 0.05) as contributors to the coefficient of variation. After including all significant factors in the final model, we found that time between measurements, hypertension, baseline FMD% and lab experience with FMD independently predicted brachial artery variability (total R = 0.202). CONCLUSION: Although FMD% showed good reproducibility, larger variation was observed in conditions with longer time between measurements, hypertension, less experience and lower baseline FMD%. Accounting for these factors may improve FMD% variability. 01 september 2016

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.

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.

Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

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.

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

Increased arterial stiffness is associated with cardiovascular disease. Its applicability in individual patient management, however, is limited due to lack of reliable methods. We developed a method to measure arterial stiffness by means of local pulse wave velocity (PWV), using multiple M-mode ultrasound and the dicrotic notch (PWVdn) rather than the systolic foot (PWVsf) as time-reference point.Systolic foot and dicrotic notch were determined in 14 simultaneously recorded distension waveforms obtained in young and older participants (mean age 26 and 59 years). Linear regression was performed on echo-line position and time-reference point, resulting in a local PWV estimate, either PWVsf or PWVdn.PWVdn, at about mean arterial pressure, had a better intra-individual variability (0.6 m/s) than PWVsf (1.1 m/s). The expected difference in stiffness between the two age categories was identified by PWVdn (P0.0001), but not by PWVsf. Moreover, in contrast to PWVsf, PWVdn showed a significant correlation with relative distension (r = 0.56) and the local distensibility coefficient (r = 0.52).PWVdn is a noninvasive and suitable measure of arterial stiffness: it has a good reproducibility, discriminates well between age groups, and correlates with local distensibility. PWVdn does not require additional assessment of distance or local pulse pressure. Furthermore, PWVdn is measured locally, at near-mean arterial pressure, thereby better reflecting the effective arterial stiffness, which determines the load the left ventricle is subjected to as it ejects blood.

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

We investigated in vitro the potential of macrophages to act as targeted vehicle for ultrasound molecular imaging. Murine bone marrow-derived macrophages (BMM), incubated for 3 h with different concentrations of perfluorohexane (PFH) emulsions, were monitored by microscopy, flow cytometry, and ultrasound. Effects of PFH loading on BMM adhesion molecule (PSGL-1, VLA-4, Mac-1, LFA-1) expression were analyzed by flow cytometry. Static adhesion of PFH loaded BMM to unstimulated and TNF-alpha stimulated b.End5 endothelial cells was assessed by microscopy. Incubation of BMM with PFH emulsions resulted in dose-dependent uptake and increased echogenicity (max. 17 dB). Flow cytometry analyses revealed no down-regulation related to PFH loading of BMM adhesion molecule expression. Endothelial adhesion remained functional, even after 24 h, although PFH loading dose-dependently attenuated static adhesion. PFH loaded BMM may potentially serve as ultrasound contrast agent for noninvasive detection of atherogenic hotspots in arteries

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.