Acute reductions in mechanical wall strain precede the formation of intimal hyperplasia in a murine model of arterial occlusive disease

ObjectiveIntimal hyperplasia (IH) continues to plague the durability of vascular interventions. Employing a validated murine model, ultrasound biomicroscopy, and speckle-tracking algorithms, we tested the hypothesis that reduced cyclic arterial wall strain results in accentuated arterial wall IH.MethodsA 9-0 suture was tied around the left mouse (n = 10) common carotid artery and a 35-gauge (outer diameter = 0.14 mm) blunt mandrel. We previously showed that mandrel removal results in a ∼78% reduction in diameter and ∼85% reduction in flow, with subsequent delayed induction of IH by day 28. Preoperative, postoperative day-4 (before measurable IH), and postoperative day-27 circumferential wall strains were measured in locations 1, 2, and 3 mm proximal to the stenosis and in the same locations on the contralateral (nonstenosed) carotid. At postoperative day 28, arteries were perfusion fixed and arterial wall morphology was assessed microscopically in the same regions.ResultsStrains were the same in all locations preoperatively. Wall strain was decreased in all regions proximal to the stenosis by day 4 (0.26 ± 0.01 to 0.11 ± 0.02; P < .001), while strains remained unchanged for the contralateral artery (P = .45). No statistical regional differences in mean strain or IH were noted at any time point for the experimental or contralateral artery. Based on the median, regions were divided into those with low strain (≤0.1) and high strain (>0.1). Average preoperative strains in both groups were the same (0.27 ± 0.09 and 0.27 ± 0.08). All segments in the low-strain group (n = 13) demonstrated significant IH formation by day 28, while only 31% of the high strain group demonstrated any detectable IH at day 28. (Mean low-strain intimal thickness = 32 ± 20 μm, high strain = 8.0 ± 16 μm; P < .01). Changes in cross-sectional area at diastole drove the reduction in strain in the low-strain group, increasing significantly from preoperatively to day 4 (P = .04), while lumen cross-section at systole remained unchanged (P = .46). Cross-sectional area at diastole and systole in the high-strain group remained unchanged from preoperatively to day 4 (P = .67).ConclusionsEarly reduction in arterial wall strain is associated with subsequent development of hemodynamically induced IH.

Clinical RelevanceIntimal hyperplasia limits the durability of vascular interventions such as angioplasties, bypasses, dialysis access grafts, and endarterectomies. Utilizing high-frequency ultrasound to determine mechanical wall strain in mice at the very earliest stages of intimal hyperplasia in a preclinical model, we find that low strain precedes the development of intimal hyperplastic lesions. Additionally, we demonstrate that decreases in wall strain are due primarily to early increases in the diastolic area of the vessel lumen, while systolic areas remain unchanged. Manipulation of wall strain stands as a potential approach to limit the development of intimal hyperplasia.