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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.).

BACKGROUND Pulse wave velocity (PWV) is blood pressure (BP) dependent, leading to the development of the BP-corrected metrics cardio-ankle vascular index (CAVI) and CAVI0. We aimed to assess risk prediction by heart-to-ankle PWV (haPWV), CAVI, and CAVI0 in a US population. METHODS We included 154 subjects (94.8% male; 47.7% African American) with and without heart failure (HF). Left and right haPWV, CAVI, and CAVI0 were measured with the VaSera 1500N device. We prospectively followed participants for a mean of 2.56 years for the composite endpoint death or HF-related hospital admission (DHFA). RESULTS Left and right haPWV, CAVI, and CAVI0 values did not differ significantly. In unadjusted analyses, haPWV (left standardized hazard ratio [HR] = 1.51, P = 0.007; right HR = 1.66, P = 0.003), CAVI (left HR = 1.45, P = 0.012; right HR = 1.58, P = 0.006), and CAVI0 (left HR = 1.39, P = 0.022; right HR = 1.44, P = 0.014) significantly predicted DHFA. Predictive ability showed a decreasing trend from haPWV to CAVI to CAVI0; in line with the increasing amount of BP correction in these metrics. In Cox models, right-sided metrics showed a trend toward stronger predictive ability than left-sided metrics. After adjustment for baseline HF status, the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, and systolic BP, right haPWV (HR = 1.58, P = 0.025) and CAVI (HR = 1.44, P = 0.044), but no other stiffness metrics, remained predictive. CONCLUSIONS Although conceptually attractive, BP-corrected arterial stiffness metrics do not offer better prediction of DHFA than conventional arterial stiffness metrics, nor do they predict DHFA independently of systolic BP. Our findings support PWV as the primary arterial stiffness metric for outcome prediction.

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.

Objectives Increased central artery stiffness associates with cardiovascular disease. Among other factors, hypertension and aging are strong contributors to central artery stiffening, yet it has been difficult to separate their effects. Herein, we study isolated and combined effects of hypertension and aging on central artery remodeling in multiple mouse models as a function of sex. Methods We biomechanically phenotyped the aorta as a function of two different methods of inducing hypertension [infusion of angiotensin II (AngII) or combining a high salt diet with inhibition of endothelial-derived nitric oxide synthase using L-NAME] in male and female wild-type and fibulin-5 null mice, the latter of which models aspects of aortic aging. Results Despite increasing blood pressure similarly, salt + L-NAME led to adaptive and maladaptive remodeling in the abdominal and thoracic aorta, respectively, whereas AngII caused luminal dilatation but little remodeling of the wall. Importantly, effects of aging were more dramatic than those resulting from induced hypertension and, consequently, superimposing hypertension on aging led to modest additional changes in luminal radius and wall thickness, though wall stress and stiffness increased mainly because of the elevated pressure. Conclusion Our results suggest that effects of hypertension on aortic remodeling are modest when superimposed on aging in mice, largely independent of sex. These findings are consistent with general observations in humans and in spontaneously hypertensive rats, though separated here for the first time in a rodent model characterized by a severe loss of elastic fiber integrity similar to that found in the aged human aorta.

Individuals with type 2 diabetes mellitus (T2DM) have a greater blood pressure (BP) response to acute maximal exercise compared to those without T2DM; however, whether they exhibit a different arterial stiffness response to maximal exercise has yet to be explored. Adults with (n=66) and without T2DM (n=61) underwent an arterial stress test: at rest and immediately postexercise, carotid-femoral pulse wave velocity, the gold standard measure of arterial stiffness, brachial BP, heart rate, and other hemodynamic measurements were assessed. Linear regression models were used to evaluate between-group differences at rest, and the response to exercise (postexercise value), adjusting for covariates including BP and heart rate when relevant, and the corresponding baseline value of each parameter. All participants (mean±SD: age 59.3±10.6 years; body mass index 31.2±3.9 kg/m 2 ) had hypertension (mean BP 130±14/80±9 mm Hg). At rest, participants with T2DM had significantly higher carotid-femoral pulse wave velocity (10.3±2.7 versus 9.1±1.9 m/s), heart rate (69±11 versus 66±10 beats/min), and lower diastolic BP (79±9 versus 83±9 mm Hg), but systolic BP (129±15 versus 131±13 mm Hg) was similar. In response to exercise, participants with T2DM showed greater increases in carotid-femoral pulse wave velocity (1.6 [95% CI, 0.4–2.9 m/s]) and systolic BP (9 [95% CI, 1–17 mm Hg]) than participants without T2DM. A greater proportion of participants with T2DM had a hypertensive response to exercise compared to participants without T2DM (n=23, 35% versus n=11, 18%; P =0.033). By incorporating exercise as a vascular stressor, we provide evidence of a greater increase in arterial stiffness in individuals with T2DM, independently of resting arterial stiffness, and the BP postexercise.

The arterial wall is a composite material of elastin, collagen, and extracellular matrix with acutely modifiable material properties through the action of smooth muscle cells. Therefore, arterial stiffness is a complex parameter that changes not only with long-term remodeling of the wall constituents but also with acute contraction or relaxation of smooth muscle or with changes in the acute distending pressure to which the artery is exposed. It is not possible to test all these aspects using noninvasive or even invasive techniques in humans. Full characterization of the mechanical properties of the artery and the specific arterial factors causing changes to stiffness with disease or modified lifestyle currently require animal studies. This article summarizes the major in vivo and ex vivo techniques to measure the different aspects of arterial stiffness in animal studies.

BACKGROUND Aortic stiffness as measured by carotid–femoral pulse wave velocity (cfPWV) is known to depend on blood pressure (BP), and this dependency may change with age. Therefore, the hydrostatic BP gradient resulting from a change in body posture may elicit a cfPWV change that is age-dependent. We aimed to analyze the relationship between BP gradient—induced by head-up body tilting—and related changes in cfPWV in individuals of varying age. METHODS cfPWV and other hemodynamic parameters were measured in 30 healthy individuals at a head-up tilt of 0° (supine), 30°, and 60°. At each angle, the PWV gradient and resulting cfPWV were also estimated (predicted) by assuming a global nonlinear, exponential, pressure–diameter relationship characterized by a constant β0, and taking into account that (diastolic) foot-to-foot cfPWV acutely depends on diastolic BP. RESULTS cfPWV significantly increased upon body tilting (8.0 ± 2.0 m/s supine, 9.1 ± 2.6 m/s at 30°, 9.5 ± 3.2 m/s at 60°, P for trend CONCLUSIONS Under a hydrostatic pressure gradient, the pulse wave traveling along the aorta undergoes an age-related, nonlinear PWV increase exceeding the increase predicted from BP dependency.

[EN] Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation., This work was supported by grants from NIH (grant nos. R01HL105297, P01 HL134605, U01 HL142518, R01 HL146723), Netherlands Organisation for Scientific Research (grant no. Rubicon 452172006) and the European Union¿s Horizon 2020 research and innovation program (grant no. 793805)

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.

Objective: Measuring arterial pulse transit time (PTT) to estimate blood pressure (BP) without conventional brachial cuff-based measurement is not new, but is a focus of current wearable technologies research. Much research pertains to efficient, accurate sensing of artery-related waveforms, yet the relationship between PTT and BP receives less attention despite being key for accurate BP estimation. This study investigated BP/PTT calibration by quantifying anatomical site variability ( n = 10, 3 female, age 30 $\pm$ 9 years) and individual variability ( n = 103, 50 female, age 53 $\pm$ 22 years). Methods: BP and pulse wave velocity (PWV) were measured in both seated and supine. Carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and carotid-finger-volume PWV (cvPWV) were measured with the wrist and hand positioned at the level of the upper thigh to achieve the same hydrostatic pressure effect across all measurements. Results: The postural change invoked a small (4 $\pm$ 7 mmHg) change in brachial diastolic BP with an additional 27 $\pm$ 2 mmHg change in hydrostatic pressure. cfPWV decreased in the supine position ( $-$ 1.75 $\pm$ 0.17 m $\cdot$ s−1, p $\Delta$ BP/ $\Delta$ PWV) across the sample population varied from 6.6 to 98.3 mmHg $\cdot$ s $\cdot$ m−1 (mean 22 $\pm$ 14 mmHg $\cdot$ s $\cdot$ m−1) and was correlated with age, heart rate, diastolic and pulse pressure, and weight. These variables did not explain the majority of the variability ( R2 = 0.248). Conclusion: There is anatomical site and between-individual variability in the calibration term for BP estimation from PTT. Significance: Using and accurately calculating hydrostatic changes in BP within the individual may be one method to increase the accuracy of this calibration term.

The process of arteriosclerosis begins early in life, and cardiovascular risk factors identified in childhood tend to persist into adulthood. Cardio-ankle vascular index (CAVI), a recent parameter of arterial stiffness, is considered an independent predictor of cardiovascular risk. However, there are no studies reporting sex- and age-specific physiological values of CAVI in childhood. We aimed to establish reference values for CAVI and its blood pressure-corrected variant (CAVI0) in 500 healthy children and adolescents aged 7 to 19 years and to study potential relationships with anthropometric indices. Sex- and age-specific distributions of CAVI and CAVI0 values in healthy children and adolescents are presented. Boys aged 15-19 years had lower CAVI than girls, which could result from CAVI's slight blood pressure dependence. CAVI0 did not show such sex difference. Body roundness index-a novel parameter to quantify abdominal fat-was a strong anthropometric predictor of both CAVI and CAVI0. This is the first study providing pediatric age- and sex-specific reference values for arterial stiffness parameters CAVI and CAVI0. The presented data can contribute to the understanding of the evolution of these indices during childhood and adolescence. Under specific conditions, CAVI0 may offer more robust information about arterial stiffness than standard CAVI.

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

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.

To identify suitable cases and reduce failure/complication rates for percutaneous ventricular septal defect (VSD) closure, we aimed to (1) study causes of device failure and (2) compare outcomes with different VSD types and devices in a high-volume single center with limited resources. Retrospective data of 412 elective percutaneous VSD closure of isolated congenital VSDs between 2003 and 2017 were analyzed. Out of 412, 363 were successfully implanted, in 30 device implantation failed, and in 19 the procedure was abandoned. Outcome was assessed using echocardiography, electrocardiography, and catheterization data (before procedure, immediately after and during follow-up). Logistic regression analyses were performed to assess effects of age, VSD type, and device type and size on procedural outcome. Median [interquartile range] age and body surface area were 6.6 [4.1–10.9] years and 0.7 [0.5–1.0] m2, respectively. Device failure was not associated with age (p = 0.08), type of VSD (p = 0.5), device type (p = 0.2), or device size (p = 0.1). Device failure occurred in 7.6% of patients. As device type is not related to failure rate and device failure and complication risk was not associated with age, it is justifiable to use financially beneficial ductal devices in VSD position and to consider closure of VSD with device in clinically indicated children.

Background: Arterial stiffness as measured by carotid-femoral pulse wave velocity (PWV) has been shown to predict cardiovascular events [1]. However, PWV is blood pressure (BP) dependent [2,3] leading to the development of cardio-ankle vascular index (CAVI) as a more blood pressure-independent index [4] that also shows predictive ability in Asian populations [5]. Recently, CAVI was further refined into CAVI0 [6], removing residual acute blood pressure dependence [7]. The present study aims to assess risk prediction by CAVI and CAVI0 in a US population. Methods: We enrolled 156 subjects (94.8% male; 47.7% African-American) with and without heart failure. Subjects underwent arterial stiffness assessments (VaSera 1500 N, Fukuda Denshi Co., Tokyo, Japan). Left (L-CAVI) and right (R-CAVI) measurements were obtained from the device, CAVI0’s were converted from CAVI’s taking into account CAVI’s scale coefficients [8,9]. We prospectively followed participants for a mean of 2.56 years for the composite endpoint of death or heart failure related hospital admission. Results: L-CAVI and R-CAVI did not differ significantly (9.80 ± 2.11 vs 9.66 ± 1.92, p = 0.146); neither did L- CAVI0 and R-CAVI0 (16.51 ± 5.85 vs 16.15 ± 5.34, p = 0.178). In unadjusted Cox regression, R-CAVI, L-CAVI, and R-CAVI0 but not L-CAVI0 predicted outcome (Table 1). After adjustment for age, sex, race, and systolic BP, only right-sided CAVIs and CAVI0s were predictive. TableCox regression results n Standardized HR [95% CI] p Unadjusted L-CAVI 155 1.33 [1.01–1.76] 0.042 R-CAVI 156 1.52 [1.10–2.11] 0.011 L-CAVI0 155 1.28 [0.97–1.68] 0.078 R-CAVI0 156 1.39 [1.04–1.87] 0.027 Adjusted for age, sex, race, and systolic BP L-CAVI 154 1.35 [0.99–1.83] 0.06 R-CAVI 155 1.55 [1.08–2.21] 0.016 L-CAVI0 154 1.30 [0.95–1.77] 0.10 R-CAVI0 155 1.39 [1.0´–1.9´] 0.044 s-HR, standardized hazard ratio; CI, confidence interval. Discussion: We observed possible body-side differences in prediction using CAVI and CAVI0. A previous study cross-sectionally reported more pronounced body side differences in heart-to-ankle PWV related to cardiovascular disease [10]; we are unaware of published prospective studies observing this. In conclusion, both R-CAVI and R-CAVI0 predicted heart-failure related end-points.

Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue damage and an alteration of arterial structure and function. Increased arterial stiffness is a well-recognized cardiovascular risk factor independent of blood pressure levels and an intermediate endpoint for cardiovascular events. In the present review we discuss immune mediated mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening. We also show that acute inflammation predisposes the vasculature to arterial dysfunction and stiffening, and alteration of endothelial function and that chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis are accompanied by profound arterial dysfunction which is proportional to the severity of inflammation. Current findings suggest that treatment of inflammation by targeted drugs leads to regression of arterial dysfunction. There is hope that these treatments will improve outcomes for patients. CONDENSED ABSTRACT: Inflammation is a physiological response to aggression of pathogenic agents aimed at eliminating the aggressor agent and promoting healing. Excessive inflammation, however, may contribute to tissue damage and an alteration of arterial structure and function. Increased arterial stiffness is a well-recognized cardiovascular risk factor independent of blood pressure levels. In the present review we discuss (i) mechanisms by which inflammation can influence arterial physiology and lead to vascular dysfunction such as atherosclerosis and arterial stiffening, (ii) clinical models of vascular inflammation, and (iii) current evidence on anti-inflammatory therapy and regression of arterial dysfunction.

We read with great interest Alizargar et al [...]

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.

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.

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.

ObjectiveMany genetically-induced mutations affect aortic structure and function in mice, but little is known about the influence of background strain. This study quantifies the aortic phenotype in angiotensin II (AngII)-induced hypertension across different strains of wild-type mice.nnApproach and ResultsAdult male C57BL/6J and 129SvEv mice were studied before and after induction of hypertension via subcutaneous infusion of AngII (1000 ng/kg/min) for two weeks, which elevated blood pressure similarly (+31% vs. +32%, systolic). The descending thoracic aortas were placed within a custom computer-controlled biomechanical testing device and subjected to a series of isobaric vasocontraction and vasorelaxation tests as well as novel stiffness testing. Immuno-histological studies quantified medial and adventitial composition as well as CD45+ cellular infiltration. Baseline aortic geometry and biomechanical properties were similar across strains, consistent with the existence of general homeostatic mechanical targets. Nevertheless, aortic remodeling due to AngII-induced hypertension differed dramatically between strains, with gross over-adaptive remodeling (exuberant thickening of the media and adventitia) in C57BL/6J but under-adaptive remodeling in 129SvEv mice. Importantly, vasoconstrictive strength was lower in C57BL/6J than 129SvEv mice, both before and after hypertension, while CD45+ cell content was markedly higher in C57BL/6J than 129SvEv mice following hypertension.nnConclusionsGenetic modifiers likely play a key role in the different hypertensive aortic remodeling between C57BL/6J and 129SvEv mice as well as mixed C57BL/6;129SvEv mice. The lower fibrotic response in 129SvEv mice results from their lower inflammatory state but also greater aortic vasoresponsiveness to AngII, which lowers the wall-stress mechano-stimulus for remodeling. Remodeling in mixed background mice is dominated by the 129SvEv strain.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/727800v1_ufig1.gif" ALT="Figure 1">nView larger version (69K):norg.highwire.dtl.DTLVardef@b395b5org.highwire.dtl.DTLVardef@29c56aorg.highwire.dtl.DTLVardef@5fc3aborg.highwire.dtl.DTLVardef@1274308_HPS_FORMAT_FIGEXP M_FIG C_FIG

BACKGROUND: In chronic kidney disease, the enhanced aortic stiffness increases risk of cardiovascular events. Kidney transplantation (KTx) may improve aortic stiffness; however, it is unclear whether the improvement of aortic stiffness is merely the outcome of the reduction of blood pressure (BP) post-KTx. Furthermore, the long-term trajectory of aortic stiffness remains uncertain, as activation of the immune system may have a negative long-term impact on arterial wall property.METHOD: Using aortic stiffness β0 as a BP-independent stiffness parameter, and a statistical adjustment for BP, we aimed to examine the early vs. late changes in aortic stiffness, and to define the characteristics of patients with favourable and unfavourable long-term trajectories of aortic stiffness. In this longitudinal study, aortic stiffness was assessed before, 3, 6 and 24 months after KTx in 79 individuals. Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV), and aortic stiffness index β0 was obtained by applying the stiffness parameter β0 theory to cf-PWV based on Bramwell-Hill's equation using a reference pressure.RESULTS: There was an early reduction of β0 3 months after KTx (29.0 ± 2.0 to 25.8 ± 1.2, P = 0.033) followed by a gradual increase at 6 (28.0 ± 1.4, P = 0.005 vs. 3 months) and 24 months (28.3 ± 1.3, P = 0.003 vs. 3 months). A late increase in β0 was associated with higher levels of the interleukin-6 (P = 0.029) even after adjustment for potential cofounders. Using statistical adjustments for BP showed similar results.CONCLUSION: Reduction of aortic stiffness index β0 3 months after KTx suggests that KTx leads to an early de-stiffening of the intrinsic mechanical properties of aorta. However, this improvement is followed by a later stiffening, which is associated with increased interleukin-6, suggesting that activation of the immune system may be involved in arterial wall remodelling in kidney recipients.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1(mgR/mgR) mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABA(B) receptor agonist baclofen. Systemic administration of baclofen to Fbn1(mgR/mgR) mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction–related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1(mgR/mgR) mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway–based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

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.

Purpose: Investigating the biomechanical role of smooth muscle cells (SMCs) in arteries requires knowledge of their structural distributions. Compared to histology, 3D microscopy offers non-destructive ex vivo imaging under realistic conditions [1]. Robust 3D segmentation of SMCs, however, is challenging. We propose a method for automatic SMC quantification, and assessed its potential using a murine SMC apoptosis model. Methods: After euthanasia, carotid arteries (control and with induced SMC apoptosis: SM22α-hDTR [2]) were excised and mounted between micropipettes (Figure A). Nuclei were stained with SYTO41. Arteries were imaged using two-photon microscopy [1], while stretched to in vivo length and pressurised to 100 mmHg (Figure B). Image stacks were processed as follows: 1) deconvolution; 2) nuclei segmentation using vesselness filtering [3,4] (Figure C); 3) cylindrical coordinate system identification; 4) splitting of coincident nuclei, based on cores defined from groups of neighbouring voxels with similar orientations [3] (Figure D and E); 5) cylindrical coordinate system re-identification; and 6) cell density-distribution quantification (Figure F). Segmentation performance was assessed by comparing with manual cell counts. Figure(A) Imaging set-up illustrating acquisition of z-stack of slices. (B) Example slice of 3D stack; cell nuclei are shown in blue while elastin fibres are shown in red. (C) Segmentation results from vesselness filtering of example image stack, colours indicate separated nuclei (step 2, Methods). (D) Coinciding nuclei, corresponding with the left orange nuclei in C, shown in grey, with cell cores shown in red and blue (step 4, Methods). (E) Coinciding nuclei splitting results of nuclei shown in C. Non-split nuclei are shown in grey, while split nuclei are shown in red and blue. (F) Transmural SMC densities and cell counts for one control and one SMC apoptosis sample; manual cell counts are given between parentheses. Results: Figure E demonstrates the method’s ability to split undersegmented coinciding nuclei. Cell counts were lower in SM22α-hDTR than in control; algorithm-derived counts were comparable to manual (Figure F). The control sample showed multiple SMC layers, while the SM22α-hDTR sample showed a single SMC layer (Figure F), which was confirmed visually. Conclusion: We developed a precise tool to quantify SMC distributions in ex vivo murine arteries, to facilitate quantitative modelling of SMC biomechanics. We intend to expand the current approach to address cell orientation, shape, and size.

Background: Aging and hypertension often co-occur, which complicates distinguishing their biomechanical effects on arteries clinically. While aortic elastin (half-life ~70 years) is reduced in human aging, in mouse aging (lifespan ~2 years) it remains mostly intact. Knock-out of elastin-associated glycoprotein fibulin-5 (Fbln5−/−) in mice however yields a biomechanical phenotype that resembles human aging. Methods: Adult male and female Fbln5+/+ and Fbln5−/− mice were studied under three conditions: untreated, after 14-day 490 ng/kg/min angiotensin-II infusion (AngII), and after 13 weeks on 8%-NaCl chow + 3 g/L L-NAME drinking water (L-NAME-NaCl). After tail-cuff blood pressure (BP) measurement and euthanasia, descending thoracic (DTA) and infrarenal abdominal (IAA) aortas were dissected and tested using a computer-controlled biaxial testing device. Results: Salt+L-NAME led to adaptive remodelling (circumferential stress homeostasis) and maladaptive remodelling (lack thereof) in the IAA and DTA, respectively (figure, males), while AngII caused luminal dilatation but little remodelling of the wall. Effects of aging (Fbln5−/−) were more dramatic than those due to induced hypertension. Consequently, superimposing hypertension on aging led to modest additional changes in luminal radius and wall thickness, though increased stress and stiffness metrics due to increased pressure loading of the wall [3] Trends in females were similar to those in males. Conclusions: Effects of hypertension on aortic remodelling are modest when superimposed on aging in mice. These findings are consistent with general observations in humans [4,5], though separated here for the first time in a rodent model characterized by a severe loss of elastic fiber integrity similar to that found in the aged human aorta.

Background: Arterial stiffness (e.g., as measured by carotid-femoral pulse wave velocity (cfPWV)) changes acutely with blood pressure (BP). High cfPWV at high BP could be due to structural arterial changes or acute BP effects. Various parameters have been proposed as BP-independent parameters of arterial stiffness. These rely on assumptions to simplify theoretical calculations. This study evaluates a parameter quantifying BP dependency of cfPWV through BP manipulation, avoiding assumptions and mathematical derivations. Methods: Brachial BP and cfPWV (SphygmoCor XCEL, AtCor Medical, Australia) were assessed in seated and supine position. The postural change invokes a systemic and hydrostatic BP change, thus changing cfPWV. ΔcfPWV/ΔBP was calculated. Repeatability was assessed in 25 participants (28 ± 11 years (mean ± SD), 52% female) across two visits on separate days. Cross-sectional correlation with age, gender, height, weight, seated BP, and supine cfPWV was assessed by stepwise linear regression across 135 participants (49 ± 23 years, 48% female). Results: Mean ΔcfPWV/ΔBP was 0.061 ± 0.025 m/s/mmHg. Repeatability showed a between-measurement difference of 0.005 ± 0.028 m/s/mmHg (8.2% error on mean). ΔcfPWV/ΔBP was cross-sectionally correlated with seated diastolic BP (standardised β = –0.506, p < 0.001), systolic BP (β = 0.503, p < 0.001), weight (β = –0.220, p = 0.006), and heart rate (β = 0.178, p = 0.039) (model p < 0.05, r2 = 0.264). Conclusion: ΔcfPWV/ΔBP showed fair repeatability. Notwithstanding accounting for BP, it correlated with typical long-term modifiers of arterial stiffness such as chronic elevated BP and weight. Further studies are required to validate if dividing ΔcfPWV by ΔBP, following acute intervention, creates an acceptable BP-independent arterial stiffness variable before the parameter is investigated for cardiovascular risk prediction to evaluate its clinical utility.

Background: Many genetic mutations affect aortic structure and function in mice, but little is known about the influence of background strain. We compared the biomechanical, structural, and gene expression responses of C57BL/6J and 129SvEv aortas to angiotensin II (AngII)-induced hypertension. Methods: After AngII infusion (14-day, 1000 ng/kg/min) and euthanasia, excised thoracic aortas were characterized functionally using isobaric vasoactive and cyclic passive stiffness tests. Immunohistochemistry quantified medial/adventitial composition and infiltration of pan-inflammatory CD45+ cells. RNA sequencing-based gene ontology, wall stress analyses, and growth and remodeling (G&R) simulations were performed to complement our mechanical findings. Results: Baseline aortic geometry, composition, and biomechanical properties, as well as AngII-induced blood pressure increases (+34% vs. +32%, systolic), were similar across strains. Yet, AngII-induced aortic remodeling differed dramatically, with gross maladaptive, fibrotic remodeling (exuberant medial/adventitial thickening) in C57BL/6J but not in 129SvEv mice (+89% vs. +12% thickness increase, p = 0.022). CD45+ cell density was markedly higher in hypertensive C57BL/6J than 129SvEv aortas (p = 0.001), while vasoconstrictive responses to AngII (causing a wall stress decrease Δσ) were greater in 129SvEv than C57BL/6J mice, both before (Δσ = −8 vs. −24%, p = 0.023) and after (Δσ = −24 vs. −46%, p < 0.001) hypertension. Gene expression, stress analyses, and G&R simulations reinforced the emergent hypothesis that mechanical stress-mediated immune processes promote maladaptive remodeling while smooth muscle contractile processes reduce wall stress and thereby protect against fibrosis (Figure). Conclusions: Differentially expressed mechano-sensitive genes play key roles in the distinct hypertensive aortic remodeling in C57BL/6J and 129SvEv mice and must be considered when comparing studies in different background strains.

Introduction: Acute, gravity-induced blood pressure (BP) changes during head-up tilt may generate concomitant variations in carotid-femoral pulse wave velocity (cf-PWV). We aimed to separate the pressure-dependent and -independent components of cf-PWV changes observed during head-up tilt. Methods: 30 healthy individuals (age 48 ± 18 years (mean ± SD), 38% males, BP 130/74 ± 12/8 mmHg) underwent head-up passive tilting at a = 0°, 30°, and 60°. BP was taken at the upper arm, constantly kept at heart level. Aortic BP was reconstructed from radial tonometry (SphygmoCor). Stiffness index b0 was estimated at 0°. 1 Assumptions: [1] from MRI2, the effective cf-PWV travel distance (ETD, 80% of straight carotid-to-femoral distance) begins at heart level; [2] the change in DBP along the aorta is predictable from the hydrostatic pressure gradient (0.73 mmHg/cm) 3; [3] cf-PWV and hydrostatic pressure relate linearly, hence predicted cf-PWV can be calculated as the average of aortic (PWVaorta, using b0 and aortic DBP) and femoral (PWVfem, using b0 and femoral DBP, corresponding to aortic DBP + (ETD × sin(a)*0.73)) PWVs. Results: Both young (24–48 years) and old (48–82 years) individuals showed increasing trends for peripheral SBP, DBP, PP, and central DBP with tilting; central SBP remained unchanged. Heart rate (HR) and cf-PWV increased with body tilt in both groups (Figure, left). b0 linearly correlated with age (R = 0.70, p < 0.01). After adjustment for HR4, observed-vs-predicted cf-PWV exponentially increased as a function of age (R2 = 0.38, p < 0.01 for quadratic equation, p = 0.04, vs. linear; Figure, right). Conclusion: With aging, the acute relationship between BP and cf-PWV becomes progressively nonlinear.

Background: Cardio-ankle vascular index (CAVI) has long been considered a measure of arterial stiffness independent of short-term changes in blood pressure (BP) [1]. Recently and theoretically, CAVI was found to be partially affected by actual BP, thus, a novel BP-corrected index, CAVI0, was proposed to diminish these effects [2,3]. Direct, repeated measures experimental data comparing CAVI’s and CAVI0’s acute blood pressure dependence is lacking. Hence, the aim of this study was to assess the effects of short-term changes of BP on CAVI0 in comparison with standard CAVI. Methods: 60 healthy adults were examined using vascular screening system VaSera 1500 N (Fukuda Denshi Co., Tokyo, Japan) during four examination periods lasting 5 minutes – baseline, cold pressor test (CPT), recovery period, and isometric handgrip exercise (IHE). CAVI and cardiovascular parameters for calculation of CAVI0 were measured after baseline, at the peak of pressor response to CPT, after recovery period, and at the peak of pressor response to IHE. CAVI, CAVI0, and mean BP were assessed for all periods. Results: CAVI significantly increased during CPT compared to baseline rest (p = 0.008), returned to baseline values during recovery period (p = 0.011 compared to CPT), and significantly increased during IHE compared to recovery period (p = 0.002). No significant changes of CAVI0 were found. CAVI significantly correlated with changes in mean BP (p = 0.012; multilevel regression); CAVI0 did not (p = 0.570). Conclusion: In this repeated measures, experimental, acute study, CAVI showed short-term blood pressure dependence, whereas CAVI0 did not.

Introduction: Although pulse wave velocity (PWV), a proxy of arterial stiffness, is a strong predictor of cardiovascular complications, it is confounded by blood pressure (BP) and heart rate at the time of examination. Furthermore, establishing whether an artery behaves stiffer or less stiff does not inform a clinician on the cause of the stiffening.Quantification of arterial stiffness: This paper focuses on BP as a confounder of PWV. We developed a method to patient-specifically determine the dependence of PWV on BP - on average 1 m/s per 10 mmHg diastolic BP - and used it to disentangle BP-dependent and -independent stiffening in hypertension and cancer patients. We furthermore showed that the socalled cardio-ankle vascular index (CAVI) d a measure deemed BP-independent d shows a residual BP-dependence that is readily correctable using a modified equation (CAVI0). Both developed methods are directly applicable to clinical measurements in individual patients.Interpretation of arterial stiffness: We developed a computer modelling procedure to disentangle contributions of the individual wall components - collagen, elastin, and smooth muscle d to arterial stiffening as observed in patients. Our model-based approach shows that with ageing, the biomechanical phenotype shifts from elastin-dominated to collagendominated load bearing.Model-based assessment of arterial wall mechanics provides a promising tool to further improve interpretation of arterial stiffness measurements in patients. Further development of such methodology applied to various mouse models may improve the understanding and interpretation of arterial stiffening in ageing and disease. (C) 2017 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.

Arterial stiffness is a marker of vascular damage. Although adiposity increases cardiovascular risk, the relationship between paediatric overweight and arterial stiffness is unclear. The study aimed to evaluate the simultaneous effect of hypertension and overweight on arterial stiffness using cardio-ankle vascular index (CAVI) and related novel, theoretically blood pressure (BP)-independent, index CAVI0. CAVI and CAVI0 were measured in 140 adolescent boys (16.0 ± 1.9 years) divided into age-matched groups: normal-weight normotensives, overweight normotensives, overweight white-coat hypertensives, and overweight essential hypertensives. Overweight normotensives had significantly lower CAVI and CAVI0 compared to normal-weight normotensives (4.81 ± 0.64 vs. 5.33 ± 0.66, p

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.

Background: Carotid-femoral pulse wave velocity (cfPWV) is predictive of cardiovascular outcomes but clinical interpretation is confounded by blood pressure (BP) interaction. This study proposes a method for PWV pressure dependency measurement suitable for routine clinical or research use. Methods: Carotid tonometry and thigh-cuff volumetric displacement allowed cfPWV measurement in the seated and supine position. Brachial oscillometry gave systemic BP. Solving simultaneous equations describing the seated and supine measurement gave hydrostatic BP change across the carotid-femoral arterial path and the pressure dependency of cfPWV. Stepwise multiple linear regression quantified the association of pressure dependency of cfPWV with demographic and cardiovascular parameters. Results: Of 88 subjects (19 to 91 years, 41 female), 4 (4.5%) had an unexpected increase in cfPWV with decreased BP from seated to supine position. Cross-sectional analysis in the remaining cohort showed blood pressure dependency of cfPWV correlated with brachial pulse pressure (β = 0.40, p < 0.001), diastolic pressure (β = −0.33, p < 0.001), gender (β = 0.25 for female/male = 1/0, p = 0.010), and heart rate (β = 0.23, p = 0.033). There was no correlation with supine cfPWV nor age. Average pressure dependency of cfPWV was 0.6±0.3 m/s per 10 mmHg (range of 0.09 to 1.5 m/s per 10 mmHg). Average change in transmural BP across the carotid-femoral arterial path was 20±7 mmHg (diastolic BP change 4±7 mmHg; hydrostatic BP change 16±2 mmHg). Conclusions: Changing from seated to supine position imparts a BP change across the carotid- femoral arterial path, the majority of the effect being hydrostatic. Measuring cfPWV in these two stable BP positions allows calculation of the BP dependency of cfPWV.

A strong association between functional bladder disorders and bladder sensation is well-known, with a relationship between malfunctioning detrusor muscle and abnormal sensation arising from the suburothelium and the lamina propria (LP), has been suggested. However, the exact underlying pathophysiology of these bladder disorders is not completely understood. Therefore, it is important to gain knowledge on sensory innervation of the urinary bladder in order to understand the neural network function in healthy and diseased bladder. In the present study we aim at the development of a computer-assisted method for 3D-tracking of sensory innervation in the murine bladder mucosa using two-photon laser scanning microscopy (TPLSM). TPLSM was performed on 10 fixed, stained (CGRP) bladder samples in both the trigone and dome. Nerve tracking was performed in subvolumes (6.3 +/- 2.9 10(6) mu m(3); median +/- IQR) of 22 stacks with determining total nerve length, nerve segment lengths, curviness, straightness, and locations of branching and ending points in the lamina propria (LP). The results show that the highest concentration of afferent fibres was found at the urothelium-LP interface. Nerve curviness, a presumed indicator of nerve activity, showed an equal value throughout the complete LP. We found a significantly higher median nerve segment length in the LP of the trigone and significantly more curved nerves in the dome of the bladder. This indicates an adaptation to, or an involvement in the detection of, bladder volume changes. Conclusively, we successfully developed a computer-assisted method for 3D tracking of sensory nerve fibres in the LP of the murine bladder wall. (C) 2017 Elsevier B.V. All rights reserved.

OBJECTIVES Sildenafil has strong cardiac preconditioning properties in animal studies and has a safe side-effect profile in children. Therefore, we evaluated the application of Sildenafil preconditioning to reduce myocardial ischaemia/reperfusion injury in children undergoing surgical ventricular septal defect (VSD) closure. METHODS This is a randomized, double-blind study. Children (1-17 years) undergoing VSD closure were randomized into three groups: placebo (Control group), preconditioning with 0.06 mg/kg (Sild-L group) and 0.6 mg/kg Sildenafil (Sild-H group). PRIMARY ENDPOINT troponin release. CK-MB, Troponin I, inflammatory response (IL-6 and TNF-α), bypass and ventilation weaning times, inotropy score and echocardiographic function were assessed. Data expressed as median (range), and a value of P < 0.05 was considered significant. RESULTS Thirty-nine patients were studied (13/group). Aortic cross-clamp time was similar [27 (18-85) and 27 (12-39) min] in the Control and Sild-L groups, respectively, but significantly longer [39 (20-96) min] in the Sild-H group when compared with the Control group. Area under the curve of CK-MB release was 1105 (620-1855) h ng/ml in the Control group, 1672 (564-2767) h ng/ml in the Sild-L group and was significantly higher in the Sild-H group [1695 (1252-3377) h ng/ml] when compared with the Control group. There were no significant differences in inflammatory response markers, cardiopulmonary bypass and ventilation weaning times, inotropy scores and echocardiographic function between the groups. CONCLUSIONS In this small study, Sildenafil failed to reduce myocardial injury in children undergoing cardiac surgery, nor does it alter cardiac function, inotropic needs or postoperative course. A subclinical increase in cardiac enzyme release after Sildenafil preconditioning cannot be excluded. CLINICAL TRIALS REGISTRY CTRI/2014/03/004468.

Vascular assessment is becoming increasingly important in the diagnosis of cardiovascular diseases. In particular, clinical assessment of arterial stiffness, as measured by pulse wave velocity (PWV), is gaining increased interest due to the recognition of PWV as an influential factor on the prognosis of hypertension as well as being an independent predictor of cardiovascular and all-cause mortality. Whilst age and blood pressure are established as the two major determinants of PWV, the influence of heart rate on PWV measurements remains controversial with conflicting results being observed in both acute and epidemiological studies. In a majority of studies investigating the acute effects of heart rate on PWV, results were confounded by concomitant changes in blood pressure. Observations from epidemiological studies have also failed to converge, with approximately just half of such studies reporting a significant blood-pressure-independent association between heart rate and PWV. Further to the lack of consensus on the effects of heart rate on PWV, the possible mechanisms contributing to observed PWV changes with heart rate have yet to be fully elucidated, although many investigators have attributed heart-rate related changes in arterial stiffness to the viscoelasticity of the arterial wall. With elevated heart rate being an independent prognostic factor of cardiovascular disease and its association with hypertension, the interaction between heart rate and PWV continues to be relevant in assessing cardiovascular risk.

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

Objective: This study examines effects of high salt diet on arterial blood pressure and aortic function in rats. Methods: Sprague-Dawley rats were fed either high salt content chow or normal chow from weaning. Weight, tail-cuff systolic blood pressure (SBP), water and food intake, and urine output were measured with age. At 16 weeks, rats were anaesthetised and thoracic and abdominal aortic blood pressure measured across a mean arterial pressure range of 60 to 150 mmHg, induced via intra-venous infusion of phenylephrine and sodium nitroprusside. Aortic pulse wave velocity (aPWV) and thoracic to abdominal aortic pulse pressure amplification (PPA) were calculated. Post-mortem weights of the left ventricle and kidneys were recorded. Statistical comparison between groups across the blood pressure range was by robust analysis of covariance. Results: Rats on a high salt diet had lower weights (p=0.04) but similar body mass index. Food intake was similar whilst water intake was greater on a high salt diet, with correspondingly greater urine output. Tail-cuff SBP was higher in rats on a high salt diet. There was no left ventricular hypertrophy (p=0.16) but greater kidney mass in high salt rats (p=0.01). High salt diet resulted in higher aPWV (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