Associations of markers of arterial stiffness and remodeling with new-onset type 2 diabetes mellitus

Funding Acknowledgements Type of funding sources: None. Background. Arterial stiffness/remodeling results in impaired blood flow and, eventually, decreased glucose disposal in peripheral tissues and increased blood glucose. Besides, increased arterial stiffness/remodeling may lead to hypertension, as a potential reciprocal risk factor for type 2 diabetes mellitus (T2D). We, therefore, hypothesized that increased arterial stiffness/remodeling is associated with an increased risk of T2D. Purpose. To study the associations between arterial stiffness/remodeling and incident T2D. Methods. We used the prospective population-based Rotterdam Study. Common carotid arterial properties were ultrasonically determined in plaque-free areas. Aortic stiffness was estimated by carotid-femoral pulse wave velocity (cf_PWV), carotid stiffness was estimated by the carotid distensibility coefficient (carDC). Arterial remodeling was estimated by carotid artery lumen diameter (carDi), carotid intima-media thickness (cIMT), mean circumferential wall stress (CWSmean), and pulsatile circumferential wall stress (CWSpuls). Cox proportional hazard regression analysis was used to estimate the associations between arterial stiffness/remodeling and the risk of incident T2D, adjusted for age, sex, cohort, mean arterial pressure (MAP), antihypertensive medications, heart rate, non- high-density lipoprotein (HDL)-cholesterol, lipid-lowering medications, and smoking. We included interaction terms in the fully adjusted models to study whether any significant associations were modified by sex, age, blood glucose, or MAP. Spearman correlation analyses were applied to examine the correlations between measurements of arterial stiffness/remodeling and glycemic traits. Results. We included 3,055 individuals free of T2D at baseline (mean (SD) age, 67.2 (7.9) years). During a median follow-up of 14.0 years, 395 (12.9%) T2D occurred. After adjustments, higher cf_PWV (hazard ratio (HR),1.18; 95%CI:1.04-1.35), carDi (1.17; 1.04-1.32), cIMT (1.15; 1.01-1.32), and CWSpuls (1.28; 1.12-1.47) were associated with increased risk of incident T2D. After further adjustment for the baseline glucose, the associations attenuated but remained statistically significant. Sex, age, blood glucose, or MAP did not modify the associations between measurements of arterial stiffness/remodeling, and incident T2D. Among the population with prediabetes at baseline (n = 513) compared to the general population, larger cIMT was associated with a greater increase in the risk of T2D. Most measurements of arterial stiffness/remodeling significantly but weakly correlated with baseline glycemic traits, particularly with blood glucose. Conclusions. Our study suggests that greater arterial stiffness/remodeling is independently associated with an increased risk of T2D development. Blood glucose and hypertension do not seem to play significant roles in these associations. Further studies should disentangle the underlying mechanism that links arterial stiffness/remodeling and T2D.

Biomechanical Forces and Atherosclerosis: From Mechanism to Diagnosis and Treatment

: The article provides an overview of current views on the role of biomechanical forces in the pathogenesis of atherosclerosis. The importance of biomechanical forces in maintaining vascular homeostasis is considered. We provide descriptions of mechanosensing and mechanotransduction. The roles of wall shear stress and circumferential wall stress in the initiation, progression and destabilization of atherosclerotic plaque are described. The data on the possibilities of assessing biomechanical factors in clinical practice and the clinical significance of this approach are presented. The article concludes with a discussion on current therapeutic approaches based on the modulation of biomechanical forces.

The complex distribution of arterial system mechanical properties, pulsatile hemodynamics, and vascular stresses emerges from three simple adaptive rules

Arterial mechanical properties, pulsatile hemodynamic variables, and mechanical vascular stresses vary significantly throughout the systemic arterial system. Although the fundamental principles governing pulsatile hemodynamics in elastic arteries are widely accepted, a set of rules governing stress-induced adaptation of mechanical properties can only be indirectly inferred from experimental studies. Previously reported mathematical models have assumed mechanical properties adapt to achieve an assumed target stress “set point.” Simultaneous prediction of the mechanical properties, hemodynamics, and stresses, however, requires that equilibrium stresses are not assumed a priori. Therefore, the purpose of this work was to use a “balance point” approach to identify the simplest set of universal adaptation rules that simultaneously predict observed mechanical properties, hemodynamics, and stresses throughout the human systemic arterial system. First, we employed a classical systemic arterial system model with 121 arterial segments and removed all parameter values except vessel lengths and peripheral resistances. We then assumed vessel radii increase with endothelial shear stress, wall thicknesses increase with circumferential wall stress, and material stiffnesses decrease with circumferential wall stress. Parameters characterizing adaptive responses were assumed to be identical in all arterial segments. Iteratively predicting local mechanical properties, hemodynamics, and stresses reproduced five trends observed when traversing away from the aortic root towards the periphery: decrease in lumen radii, wall thicknesses, and pulsatile flows and increase in wall stiffnesses and pulsatile pressures. The extraordinary complexity of the systemic arterial system can thus arise from independent adaptation of vessels to local stresses characterized by three simple adaptive rules.

Abstract 232: The P2Y2 Nucleotide Receptor Mediates Blood Flow Recovery Following Hindlimb Ischemia in Mice

Objectives: Arteriogenesis is a process by which small resistance vessels mature into large caliber collateral arteries in response to arterial occlusive disease. The forces stimulating arteriogenesis nclude shear stress and circumferential wall stress. Nucleotides are released from cells in response to mechanical stimuli and may activate nucleotide receptors. Thus, we hypothesize that the P2Y 2 nucleotide receptor, expressed by vascular cells, mediates arteriogenesis. Methods: C57Bl6 NJ (WT) and P2Y 2 R KO mice (n=8/group) underwent unilateral femoral artery ligation (FAL). Perfusion was measured immediately after ligation and at 3, 7, 14, 21, and 28 days using laser Doppler perfusion imaging (LDPI). Mice were sacrificed at 28 days and tibialis anterior collected for histology. Results: LDPI of the ischemic hindlimb showed a return to baseline perfusion in WT mice (Figure). P2Y 2 KO mice recovered to <40% of baseline. Additionally, 4/8 P2Y 2 KO mice developed wounds of the ischemic limbs vs. 0/8 of WT mice. Histological analysis of tibialis anterior demonstrated regenerating myocytes in 3/4 P2Y 2 KO vs. 1/4 WT animals. By immunohistochemistry, angiogenesis was significantly increased in P2Y 2 KO with a CD31+cell/myocyte ratio of 1.974 vs. 1.314 of WT (p=0.05). There was also greater inflammation in P2Y 2 KO with CD45+ cell infiltration over 3-fold that of WT (p<0.001). Conclusion: The P2Y 2 nucleotide receptor is important for blood flow recovery in a murine model of FAL. P2Y 2 KO mice also demonstrated delayed muscle regeneration with greater angiogenesis and inflammation in ischemic limbs. Further molecular analyses are needed to elucidate the mechanisms involved.

Role of shear stress and stretch in vascular mechanobiology

Blood vessels are under constant mechanical loading from blood pressure and flow which cause internal stresses (endothelial shear stress and circumferential wall stress, respectively). The mechanical forces not only cause morphological changes of endothelium and blood vessel wall, but also trigger biochemical and biological events. There is considerable evidence that physiologic stresses and strains (stretch) exert vasoprotective roles via nitric oxide and provide a homeostatic oxidative balance. A perturbation of tissue stresses and strains can disturb biochemical homeostasis and lead to vascular remodelling and possible dysfunction (e.g. altered vasorelaxation, tone, stiffness, etc.). These distinct biological endpoints are caused by some common biochemical pathways. The focus of this brief review is to point out some possible commonalities in the molecular pathways in response to endothelial shear stress and circumferential wall stretch.

Microfibrillar Elastic Polymer Wrapping of Rat Vena Cava for the Study of Engineered Arterial Vein Grafts

The autologous saphenous vein graft remains the graft of choice for 95% of surgeons performing coronary artery or peripheral bypass procedures. Within the first 5 years after implantation, 20%–40% of arterial vein grafts (AVG) fail due to intimal hyperplasia (IH)1. This adverse pathological response by AVGs may be in part due to their abrupt exposure to the significantly elevated circumferential wall stress associated with the arterial system2. We believe that if an AVG is given an ample opportunity to adapt and remodel to the stresses of the arterial environment, cellular injury may be reduced, thus limiting the initiating mechanisms of IH.