Arterial remodeling refers to the structural and functional changes of the vessel wall that occur in response to disease, injury, or aging. Vascular smooth muscle cells (VSMC) play a pivotal role in regulating the remodeling processes of the vessel wall. Phenotypic switching of VSMC involves oxidative stress-induced extracellular vesicle release, driving calcification processes. The VSMC phenotype is relevant to plaque initiation, development and stability, whereas, in the media, the VSMC phenotype is important in maintaining tissue elasticity, wall stress homeostasis and vessel stiffness. Clinically, assessment of arterial remodeling is a challenge; particularly distinguishing intimal and medial involvement, and their contributions to vessel wall remodeling. The limitations pertain to imaging resolution and sensitivity, so methodological development is focused on improving those. Moreover, the integration of data across the microscopic (i.e., cell-tissue) and macroscopic (i.e., vessel-system) scale for correct interpretation is innately challenging, because of the multiple biophysical and biochemical factors involved. In the present review, we describe the arterial remodeling processes that govern arterial stiffening, atherosclerosis and calcification, with a particular focus on VSMC phenotypic switching. Additionally, we review clinically applicable methodologies to assess arterial remodeling and the latest developments in these, seeking to unravel the ubiquitous corroborator of vascular pathology that calcification appears to be.

Our study demonstrates that the innate pressure-dependence of arterial stiffness may have implications for the clinical use of arterial stiffness measurements, both in risk assessment and in treatment monitoring of individual patients. We propose a number of clinically feasible approaches to account for the blood pressure effect on PWV measurements.

β and CAVI as currently implemented are inherently BP-dependent, potentially leading to erroneous conclusions in arterial stiffness trials. BP-independent forms are presented to readily overcome this problem.

We estimated age and sex-specific percentiles of carotid stiffness in a healthy population and assessed the association between cardiovascular risk factors and carotid distensibility coefficient Z-scores, which enables comparison of carotid stiffness values between (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures.

PWVdn is a noninvasive and suitable measure of arterial stiffness: it has a good reproducibility, discriminates well between age groups, and correlates with local distensibility. PWVdn does not require additional assessment of distance or local pulse pressure. Furthermore, PWVdn is measured locally, at near-mean arterial pressure, thereby better reflecting the effective arterial stiffness, which determines the load the left ventricle is subjected to as it ejects blood.

BackgroundCardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded.MethodsIn a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets.ResultsIn the MOF group serum total cholesterol and LDL decreased significantly (P≤0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05) in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P≤0.05).ConclusionOur integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 weeks supplementation with 200 mg/d MOF in humans.Trial RegistrationClinicalTrials.gov NCT00742287

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

Abstract-Arterial stiffening plays an important role in the development of hypertension and cardiovascular diseases. The intrinsically nonlinear (ie, pressure-dependent) elastic behavior of arteries may have serious consequences for the accuracy and interpretation of arterial stiffness measurements and, ultimately, for individual patient management. We determined aortic pressure and common carotid artery diameter waveforms in 21 patients undergoing cardiac catheterization. The individual pressure-area curves were described using a dual exponential analytic model facilitating noise-free calculation of incremental pulse wave velocity. In addition, compliance coefficients were calculated separately in the diastolic and systolic pressure ranges, only using diastolic, dicrotic notch, and systolic data points, which can be determined noninvasively. Pulse wave velocity at systolic pressure exhibited a much stronger positive correlation with pulse pressure (PϽ0.001) and age (Pϭ0.012) than pulse wave velocity at diastolic pressure. Patients with an elevated systolic blood pressure (Ͼ140 mm Hg) had a 2.5-times lower compliance coefficient in the systolic pressure range than patients with systolic blood pressures Ͻ140 mm Hg (Pϭ0.002). Most importantly, some individuals, with comparable age or pulse pressure, had similar diastolic but discriminately different systolic pulse wave velocities and compliance coefficients. We conclude that noninvasive assessment of arterial stiffness could and should discriminate between systolic and diastolic pressure ranges to more precisely characterize arterial function in individual patients. Key Words: arterial structure and compliance Ⅲ pulse wave velocity Ⅲ blood pressure measurement Ⅲ systolic hypertension Ⅲ carotid arteries D ecreased elasticity of the arterial wall plays an important role in the development of hypertension and related cardiovascular complications, such as heart failure, stroke, and renal failure. 1-4 Therefore, noninvasive assessment of arterial stiffness has recently entered the European Society of Hypertension/European Society of Cardiology guidelines for the management of hypertension. 5 Basic studies have shown that the elastic behavior of the arterial system is nonlinear, that is, arterial stiffness is pressure dependent. 6 -11 This intrinsic property of the arterial system may have serious consequences for the quantitative assessment of arterial stiffness, and changes therein, in response to age, 12,13 physiological stress, 7 and possibly antihypertensive treatment. 14,15 Currently, arterial stiffness is assessed noninvasively either at the diastolic pressure level (aortic or carotid-femoral pulse wave velocity [PWV]) or estimated as an average over the diastolic-systolic pressure range. In the latter case, distensibility and compliance coefficients are calculated as, respectively, the relative and absolute changes in the cross-sectional area normalized to pulse pressure from diastolic minimum to systolic peak, 16 tacitly assuming a linear pressure-area relatio...