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BACKGROUND: Arterial stiffness predicts cardiovascular outcomes. The complement system, particularly the alternative complement pathway, has been implicated in cardiovascular diseases. We herein investigated the associations of factor D, the rate-limiting protease of the alternative pathway, and C3, the central complement component, with arterial stiffness.METHODS: In 3019 population-based participants (51.9% men, 60.1 ± 8.2 years, 27.7% type 2 diabetes [T2D], oversampled]), we measured carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC) and carotid Young's elastic modulus (YEM), and plasma concentrations of factors D and C3. We conducted multiple linear regression to investigate the association of factors D and C3 (main independent variables, standardized) with cfPWV (primary outcome) and DC and YEM (secondary outcomes), adjusted for potential confounders.RESULTS: Per SD higher factors D and C3, cfPWV was 0.41 m/s [95% confidence interval: 0.34; 0.49] and 0.33 m/s [0.25; 0.41] greater, respectively. These associations were substantially attenuated when adjusted for age, sex, education, mean arterial pressure, and heart rate (0.08 m/s [0.02; 0.15] and 0.11 m/s [0.05; 0.18], respectively), and were not significant when additionally adjusted for T2D, waist circumference and additional cardiovascular risk factors (0.06 m/s [-0.01; 0.13] and 0.01 m/s [-0.06; 0.09], respectively). Results were comparable for carotid YEM and DC. In persons with T2D, but not in those without, the association between factors D and cfPWV was significant in the fully adjusted model (0.14 m/s, [0.01; 0.27], P = 0.038, Pinteraction CONCLUSION: The strong association of plasma factors D and C3 with arterial stiffness in this population-based cohort was not independent of T2D and other metabolic risk factors. Our data suggest that a possible causal pathway starting from alternative complement activation may via hypertension and T2D contribute to greater arterial stiffness.

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.

Arteries exhibit fully nonlinear viscoelastic behaviours (i.e. both elastically and viscously nonlinear). While elastically nonlinear arterial models are well established, effective mathematical descriptions of nonlinear viscoelasticity are lacking. Quasi-linear viscoelasticity (QLV) offers a convenient way to mathematically describe viscoelasticity, but its viscous linearity assumption is unsuitable for whole-wall vascular applications. Conversely, application of fully nonlinear viscoelastic models, involving deformation-dependent viscous parameters, to experimental data is impractical and often reduces to identifying specific solutions for each tested loading condition. The present study aims to address this limitation: By applying QLV theory at the wall constituent rather than at the whole-wall level, the deformation-dependent relative contribution of the constituents allows to capture nonlinear viscoelasticity with a unique set of deformation-independent model parameters. Five murine common carotid arteries were subjected to a protocol of quasi-static and harmonic, pseudo-physiological biaxial loading conditions to characterise their viscoelastic behaviour. The arterial wall was modelled as a constrained mixture of an isotropic elastin matrix and four families of collagen fibres. Constituent-based QLV was implemented by assigning different relaxation functions to collagen- and elastin-borne parts of the wall stress. Nonlinearity in viscoelasticity was assessed via the pressure dependency of the dynamic-to-quasi-static stiffness ratio. The experimentally measured ratio increased with pressure, from 1.03 $$\pm$$ ± 0.03 (mean $$\pm$$ ± standard deviation) at 80–40 mmHg to 1.58 $$\pm$$ ± 0.22 at 160–120 mmHg. Constituent-based QLV captured well this trend by attributing the wall viscosity predominantly to collagen fibres, whose recruitment starts at physiological pressures. In conclusion, constituent-based QLV offers a practical and effective solution to model arterial viscoelasticity.

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."

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.

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.

IntroductionPreeclampsia, an endothelial disorder of pregnancy, predisposes to remote cardiovascular diseases (CVD). Whether there is an accelerated effect of aging on endothelial decline in former preeclamptic women is unknown. We investigated if the arterial aging regarding endothelial-dependent and -independent vascular function is more pronounced in women with a history of preeclampsia as compared to women with a history of solely normotensive gestation(s).MethodsData was used from the Queen of Hearts study (ClinicalTrials.gov Identifier NCT02347540); a large cross-sectional study on early detection of cardiovascular disease among young women (≥18 years) with a history of preeclampsia and a control group of low-risk healthy women with a history of uncomplicated pregnancies. Brachial artery flow-mediated dilation (FMD; absolute, relative and allometric) and sublingually administered nitroglycerine-mediated dilation (NGMD; absolute and relative) were measured using ultrasound. Cross-sectional associations of age with FMD and NGMD were investigated by linear regression. Models were adjusted for body mass index, smoking, antihypertensive drug use, mean arterial pressure, fasting glucose, menopausal state, family history of CVD and stress stimulus during measurement. Effect modification by preeclampsia was investigated by including an interaction term between preeclampsia and age in regression models.ResultsOf the 1,217 included women (age range 22–62 years), 66.0% had a history of preeclampsia and 34.0% of normotensive pregnancy. Advancing age was associated with a decrease in relative FMD and NGMD (unadjusted regression coefficient: FMD: −0.48%/10 years (95% CI:−0.65 to −0.30%/10 years), NGMD: −1.13%/10 years (−1.49 to −0.77%/10 years)) and increase in brachial artery diameter [regression coefficient = 0.16 mm/10 years (95% CI 0.13 to 0.19 mm/10 years)]. Similar results were found when evaluating FMD and NGMD as absolute increase or allometrically, and after confounder adjustments. These age-related change were comparable in former preeclamptic women and controls (p-values interaction ≥0.372). Preeclampsia itself was independently associated with consistently smaller brachial artery diameter, but not with FMD and NGMD.ConclusionIn young- to middle-aged women, vascular aging in terms of FMD and NGMD was not accelerated in women after preeclampsia compared to normotensive pregnancies, even though former preeclamptic women consistently have smaller brachial arteries.

The Esaote MyLab70 ultrasound system has been extensively used to evaluate arterial properties. Since it is reaching end-of-service-life, ongoing studies are forced to seek an alternative, with some opting for the Esaote MyLabOne. Biases might exist between the two systems, which, if uncorrected, could potentially lead to the misinterpretation of results. This study aims to evaluate a potential bias between the two devices. Moreover, by comparing two identical MyLabOne systems, this study also aims to investigate whether biases estimated between the MyLabOne and MyLab70 employed in this study could be generalized to any other pair of similar scanners. Using a phantom set-up, we performed n = 60 measurements to compare MyLab70 to MyLabOne and n = 40 measurements to compare the two MyLabOne systems. Comparisons were performed to measure diameter, wall thickness, and distension. Both comparisons led to significant biases for the diameter (relative bias: −0.27% and −0.30% for the inter- and intra-scanner model, respectively, p < 0.05) and wall thickness (relative bias: 0.38% and −1.23% for inter- and intra-scanner model, respectively p < 0.05), but not for distension (relative bias: 0.48% and −0.12% for inter- and intra-scanner model, respectively, p > 0.05). The biases estimated here cannot be generalized to any other pair of similar scanners. Therefore, longitudinal studies with large sample sizes switching between scanners should perform a preliminary comparison to evaluate potential biases between their devices. Furthermore, caution is warranted when using biases reported in similar comparative studies. Further work should evaluate the presence and relevance of similar biases in human data.

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

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.

Mathematical modeling of pressure and flow waveforms in blood vessels using pulse wave propagation (PWP) models has tremendous potential to support clinical decision making. For a personalized model outcome, measurements of all modeled vessel radii and wall thicknesses are required. In clinical practice, however, data sets are often incomplete. To overcome this problem, we hypothesized that the adaptive capacity of vessels in response to mechanical load could be utilized to fill in the gaps of incomplete patient-specific data sets. We implemented homeostatic feedback loops in a validated PWP model to allow adaptation of vessel geometry to maintain physiological values of wall stress and wall shear stress. To evaluate our approach, we gathered vascular MRI and ultrasound data sets of wall thicknesses and radii of central and arm arterial segments of 10 healthy subjects. Reference models (i.e., termed RefModel, n = 10) were simulated using complete data, whereas adapted models (AdaptModel, n = 10) used data of one carotid artery segment only, and the remaining geometries in this model were estimated using adaptation. We evaluated agreement between RefModel and AdaptModel geometries, as well as that between pressure and flow waveforms of both models. Limits of agreement (bias +/- 2 SD of difference) between AdaptModel and RefModel radii and wall thicknesses were 0.2 +/- 2.6 mm and -140 +/- 557 mu m, respectively. Pressure and flow waveform characteristics of the AdaptModel better resembled those of the RefModels as compared with the model in which the vessels were not adapted. Our adaptation-based PWP model enables personalization of vascular geometries even when not all required data are available.NEW & NOTEWORTHY To benefit personalized pulse wave propagation (PWP) modeling, we propose a novel method that, instead of relying on extensive data sets on vascular geometries, incorporates physiological adaptation rules. The developed vascular adaptation model adequately predicted arterial radius and wall thickness compared with ultrasound and MRI estimates, obtained in humans. Our approach could be used as a tool to facilitate personalized modeling, notably in case of missing data, as routinely found in clinical settings.

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: Dysfunctional cellular mechanosensing appears central to aneurysm formation [1]. We aimed to derive material parameters of aneurysm tissue from in vivo deformations, which may increase insight into the underlying structural integrity of the pathological tissue. Methods: Videos of tracking markers (example Video in supplement, screenshot in Figure) placed on ascending aortic segments were captured alongside radial arterial blood pressure in patients undergoing open-thorax ascending thoracic aorta aneurysm (ATAA) repair (n = 5) and coronary bypass (controls; n = 2). Normalised cross-correlation was used to determine marker displacements, resulting in estimates of systolic/diastolic diameters, distensibility, and cyclic axial engineering strain. A thin-walled, cylindrical geometry was assumed, with amorphous (Neo-Hookean) and fibrous (two-family) constitutive contributions [2]. This framework was fitted to individual patient measurements, by varying parameters c (amorphous material constant), k1 and k2 (fiber stiffness and strain stiffening parameter), β (fiber angle w.r.t. circumferential direction), unloaded intact length (L), and internal radius (Ri). FigureLeft: Example of ascending aortic region of interest with tracking markers. Right: Data presented as mean ± standard deviation. SBP/DBP, systolic/diastolic blood pressure. Estimated properties are defined in the text. Results: Axial strain tended to be lower (expected) and distensibility larger (unexpected) in aneurysm than controls (Figure). However, the intrinsic pressure-dependence of distensibility must be considered when drawing conclusions related to differences in structural stiffness between both groups [3]. Material stiffness parameters (c and k1) appeared higher in aneurysm patients than in controls which is in line with previous studies in mice [4]. Conclusion: We are developing a method to determine ATAA material properties from in vivo deformations and observed increased material stiffness in ATAA.

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.

Background: Calibration of carotid artery tonometry waveforms needs to account for pulse pressure augmentation [1]. Due to its location nearer to the heart, carotid pulse pressure (carPP) is about 10 mmHg lower than brachial (brachPP) [1]. In practice, perfect applanation is hard to achieve with tonometry and thus tracking-errors may occur, leading to an exaggerated fall in the diastolic limb of the tonometry waveform. Consequently, the mean-to-diastolic difference of the waveform is underestimated, leading to an overestimation of carPP after calibration. We assessed the relationship between brachPP and carPP in 100 subjects, aged 18–80 yrs. Methods and Results: Brachial pressure (Omron) and carotid tonometry (Sphygmocor) measurements were performed by a single, highly skilled vascular technician, according to Artery Society methodological standards. CarPP was 5 ± 13 mmHg lower than brachPP. Bland-Altman analysis revealed a positive trend (r = 0.695, p < 0.0001) between the carPP–brachPP difference and their mean, with carPP being 20 mmHg lower than brachPP at a mean 40 mmHg which extended to carPP being 20 mmHg higher(!) than brachPP at a mean 80 mmHg. Accordingly, 30% of the study population showed unphysiological carPP, indicating an unrealistic i.e. reverse amplification. Even with a tolerance of +5 mmHg, still 20% of cases showed unrealistic values. Conclusion: In practice, calibrated carotid tonometry waveforms may yield unphysiological overestimations of carotid pulse pressure. This finding implies (potential) estimation errors in regression model studies on central pressure and local stiffness, suggesting brachial pulse pressure would be a valid compromise.

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.

Local biaxial deformation measurements are essential for the in-depth investigation of tissue properties and remodeling of the ascending thoracic aorta, particularly in aneurysm formation. Current clinical imaging modalities pose limitations around the resolution and tracking of anatomical markers. We evaluated a new intra-operative video-based method to assess local biaxial strains of the ascending thoracic aorta. In 30 patients undergoing open-chest surgery, we obtained repeated biaxial strain measurements, at low- and high-pressure conditions. Precision was very acceptable, with coefficients of variation for biaxial strains remaining below 20%. With our four-marker arrangement, we were able to detect significant local differences in the longitudinal strain as well as in circumferential strain. Overall, the magnitude of strains we obtained (range: 0.02–0.05) was in line with previous reports using other modalities. The proposed method enables the assessment of local aortic biaxial strains and may enable new, clinically informed mechanistic studies using biomechanical modeling as well as mechanobiological profiling.

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.

This paper aims to summarize and map contemporary views on some contentious aspects of arterial hemodynamics that have remained unresolved despite years of research. These were discussed during a workshop entitled Arterial hemodynamics: past, present and future held in London on June 14 and 15, 2016. To do this we formulated a list of potential consensus statements informed by discussion at the meeting in London and quantified the degree of agreement and invited comments from the participants of the workshop. Overall the responses and comments show a high measure of quantitative agreement with the various proposed 'consensus' statements. Taken together, these statements seem a useful basis for proceeding with a more detailed and comprehensive consensus document on the current understanding and approaches to analysis of the pulse waveform. Future efforts should be directed at identifying remaining areas of dispute and future topics for research. (C) 2017 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.