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.

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM–VSMC network.

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

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 v_s,LV and arterial stiffness on AIx. Aortic blood pressure waveforms were characterized using AIx and the reflected wave pressure amplitude ([ ], obtained using wave separation analysis). Our reference simulation (normal v_s,LV and arterial stiffness) was characterized by an AIx of 21%. A realistic reduction in v_s,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 v_s,LV and increased arterial stiffness resulted in an AIx of 54%. In a multistep parametric analysis, both v_s,LV and arterial stiffness were about equal determinants of AIx, whereas [ ] 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 v_s,LV. The [ ], 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.

$Objective:$ 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.

Macrophages may concentrate ultrasound contrast agents and exhibit selective adhesion to activated endothelium. The present study investigates in mice the potential of perfluorohexane (PFH) loaded macrophages to act as ultrasound contrast agent with high reflectivity and specifically targeted at (atherosclerotic) vascular lesions. Lung passage was evaluated with a mouse echo scanner after injection, at a slow pace or as a bolus, of varying doses of PFH-loaded and unloaded bone marrow macrophages (BMM) into the jugular vein. The interaction of PFH-loaded and unloaded BMM with TNF-α stimulated carotid artery endothelium after tail vein injection was assessed by means of intravital microscopy. High doses of jugular vein injected PFH-loaded BMM were visible with ultrasound in the pulmonary artery and detectable in the carotid artery. At intravital microscopy, tail vein injected BMM exhibited rolling and adhesion behavior at the TNF-α stimulated carotid endothelium, similar to that of native blood leukocytes. Rolling behavior was not different between PFH-loaded and unloaded BMM (p = 0.38). In vivo, perfluorohexane loaded macrophages pass the pulmonary circulation and appear on the arterial side. Moreover, they roll and adhere selectively to activated endothelium under physiological flow conditions. These findings indicate that perfluorohexane loaded BMM could be used to study processes in vivo where endothelial activation plays a role, such as atherosclerosis.